PDE9 inhibitors with imidazo triazinone backbone

ABSTRACT

This invention is directed to compounds, which are PDE9 enzyme inhibitors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The present invention also provides processes for the preparation of the compounds of formula (I). The present invention further provides a method of treating a subject suffering from a neurodegenerative disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I). The present invention further provides a method of treating a subject suffering from a psychiatric disorder comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

FIELD OF THE INVENTION

The present invention relates to cyclic guanylate monophosphate(cGMP)-specific phosphodiesterase type 9 inhibitors (hereinafterreferred to as PDE9 inhibitors) of the form3H-imidazo[5,1-f][1,2,4]triazin-4-ones for the use as a medicament.Moreover the invention relates to a pharmaceutical compositioncomprising 3H-imidazo[5,1-f][1,2,4]triazin-4-ones, as well as a processfor preparation of the compounds.

BACKGROUND OF THE INVENTION

The phosphodiesterases (PDEs) are a superfamily of enzymes thatmetabolically inactivate the ubiquitous intracellular messengers cAMPand cGMP. This function involves the PDEs in a broad range of importantcellular functions, such as immune response, memory, and vision. Thehuman genome encodes for 21 PDEs that are categorized into 11 families(Mehats C, Andersen C B, Filopanti M, Jin S L, Conti M. “Cyclicnucleotide phosphodiesterases and their role in endocrine cellsignaling.” Trends Endocrinol Metab. 2002; 13:29-35). These enzymesshare a conserved catalytic domain of approximately 300 amino acids thatis located in the C-terminal region of the protein. The N-terminalregions, which vary among different PDEs, serve regulatory functionsincluding autoinhibition of the catalytic domains or control ofsub-cellular localization (Mehats 2002). The PDEs have differentsubstrate preferences: Cyclic guanylate monophosphate (cGMP)-specificphosphodiesterase type 9 (PDE9) is a member of the PDE enzyme familythat selectively hydrolyses cGMP over cAMP (D A Fisher et al., J. Biol.Chemistry, vol. 273, No. 25, 15559-15564 (1998)). The differentsubstrate preferences, combined with different expression profiles,cellular compartmentalization, and regulation, allow the PDEs to play avery versatile role in cell signal transduction (Breer H, Boekhoff I,Tareilus E. “Rapid kinetics of second messenger formation in olfactorytransduction.” Nature. 1990; 345:65-68).

PDE9 inhibitors have been reported as useful to treat cardiovasculardisorders (WO 03/037899), and insulin resistance syndrome, hypertension,and/or type 2 diabetes (WO 03/037432) as well as for treatment ofobesity related conditions (WO/2005/041972).

Wunder F. et al (Mol. Pharmacol. 2005 December; 68(6):1775-81, 2005)report the in vitro characterization of1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one,a selective inhibitor of phosphodiesterase 9 (PDE9), which is underdevelopment for the treatment of Alzheimer's disease. This compound isreported to inhibit human (IC50=55 nM) and murine (IC50=100 nM) PDE9activity in vitro.

Over the years convincing experimental evidence has accumulatedsupporting the cognition-enhancing properties of several classes ofPDE-inhibitors (Blokland et al., 2006: “Improving memory; a role forphosphordiesterases”, Current Pharmacological Design 12, 2511-2523).

In a later study van der Staay et al. (F. Josef van der Staay,Neuropharmacology Volume 55, Issue 5, October 2008, pages 908-918)concludes that the PDE9 inhibitor1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-onemay act as a putative cognition enhancer.

WO 2012/040230 (Envivo Pharmaceuticals, Inc) is directed toimidazotriazinone compounds which are claimed to be inhibitors ofphosphordiesterease 9.

Alzheimers disease is the most common form of dementia, it is incurable,degenerative, and terminal. The typical symptoms are cognitivedifficulties, difficulties with executive functioning (such as planning,organization, mental flexibility and task coordination) as well as withperception (agnosia) and execution of movements (apraxia).

Because AD cannot be cured and is degenerative, palliative treatment ofpatients is essential.

SUMMARY OF THE INVENTION

The present invention discloses novel PDE9 inhibitors for the use as amedicament, such as in the treatment of patients suffering fromcognitive impairments, in particular cognitive impairments that relateto neurodegenerative diseases such as cortical dementia (e.g.Alzheimer's disease) or subcortical dementia, e.g. AIDS relateddementia.

The PDE9 inhibitors of the present invention have the structure I (i.e.a 3H-imidazo[5,1-f][1,2,4]triazin-4-one backbone):

wherein R2 is cyclized with either R1 or R3.

The invention relates to methods of improving conditions involving PDE9,such as cognition, in particular the invention relates to a method oftreating diseases involving cognitive difficulties, difficulties withexecutive functioning (such as planning, organization, mentalflexibility and task coordination) as well as with pereception(agnosia). The methods of improving conditions involving PDE9 and/ortreating diseases involving PDE9 comprises the administration of acompound of the present invention or a pharmaceutically acceptable salt,solvate or prodrug thereof to a patient in need thereof. The compound ofthe present invention or a pharmaceutically acceptable salt, solvate orprodrug thereof may be in the form of a pharmaceutical composition.

In a further aspect the invention relates to an improved pharmaceuticalcomposition comprising a compound of the present invention particularlyuseful for the treatment of cognitive difficulties, difficulties withexecutive functioning (such as planning, organization, mentalflexibility and task coordination) as well as with pereception(agnosia), in particular when associated neurodegenerative diseases,such as cortical or subcortical dementias, e.g. Alzheimer's disease(AD).

DETAILED DESCRIPTION OF THE INVENTION

Cognitive impairment includes a decline in cognitive functions orcognitive domains, such as, e.g., difficulties with attention, learning,memory and executive function (relevant reactions to external stimuli).Cognitive impairment also may include: deficits in attention,disorganized thinking, slow thinking, difficulty in understanding, poorconcentration, impairment of problem solving, poor memory, difficulty inexpressing thoughts and/or integrating thoughts, feelings and behaviour,and/or extinction of irrelevant thoughts, and difficulty in attentionand vigilance, verbal learning and memory, visual learning and memory,speed of processing, social cognition, reasoning and problem solving,e.g., executive functioning. There are presently no effective drugs forthe treatment of cognitive disorders on the market and there is a greatneed and demand for drugs effective in the treatment of such disorders.

Without being limited to any specific theory it is believed that themode of action of PDE9 inhibitors can be understood in the light of thefollowing neurological processes: guanylyl cyclase (alt. guanylatecyclase) converts guanosine triphosphate (GTP) to cyclic guanosinemonophosphate (cGMP), which in turn activates cGMP-dependent proteinkinase G (PKG). PKG is known to lower the threshold for the induction oflong-term potentiation (LTP), i.e. the long-lasting improvement incommunication between neurons (Zhou et al., 1994: “Role of guanylylcyclase and cGMP-dependent protein kinase in long-term potentiation”,Nature 368, 635-639). The communication between neurons takes place viathe chemical synapses (synaptic transmission) and because memories arebelieved to be stored within these synapses, LTP is considered one ofmajor cellular mechanisms that underlies cognition (Boron, W. F., 2005:Medical Physiology: A Cellular and Molecular Approach.Elsevier/Saunders, ISBN 1-4160-2328-3 and Cooke et al., 2006 “Plasticityin the human central nervous system”. Brain 129, 1659-1673). As a resulthigh levels of cGMP will eventually lead to improvement of cognition viathe activation of PKG. The level of cGMP can be increased by inhibitionof PDE9, which as mentioned above has the highest affinity for cGMP ofany of the PDEs. Accordingly, PDE9 inhibitors will improve synaptictransmission and thereby enhance cognitive performance as evidenced bythe results presented in the experimental section.

The invention will be illustrated in the following non-limitingexamples.

Embodiments According to the Invention

In a first embodiment (E1) the present invention relates to compoundshaving the structure (I) (also referred to as compounds of formula (I))

-   -   wherein R2 is cyclized with either R1 or R3,    -   wherein R1, R2 and R3 are    -   R1, when cyclized with R2, is

-   -   -   wherein R6 is selected from the group consisting of H, —CH₃,            —C₂H₅, and —C₃H₇,        -   wherein * denotes the cyclization point, and

    -   R1, when not cyclized, is selected from the group consisting of

-   -   -   H and        -   wherein R6 is selected from the group consisting of H, —CH₃,            —C₂H₅, and —C₃H₇

    -   R2 is a compound selected from the group consisting of

-   -   wherein R7 and R11 independently are selected from the group        consisting of H, —CH₃, —C₂H₅, and —C₃H₇        -   wherein * denotes the cyclization point, and    -   R3, when cyclized with R2, is

-   -   -   wherein * denotes the cyclization point, and        -   wherein R8 is selected from the group consisting of H, C₁-C₆            alkyl, branched C₃-C₆ alkyl, C₃-C₆ cycloalkyl, C₆-C₁₀ aryl,            substituted C₆-C₁₀ aryl, C₃-C₉ heteroaryl, substituted C₃-C₉            heteroaryl, C₁-C₆ alkoxy, branched C₃-C₆ alkoxy, C₃-C₆            cycloalkoxy, C₆-C₁₀ aryloxy, substituted C₆-C₁₀ aryloxy,            C₃-C₉ heteroaryloxy, substituted C₃-C₉ heteroaryloxy; and

    -   R3, when not cyclized, is

-   -   -   wherein            -   R9 is selected from the group consisting of H, —CH₃, and                —C₂H₅; and            -   R10 is selected from the group consisting of C₆-C₁₀                aryl, substituted C₆-C₁₀ aryl, C₃-C₉ heteroaryl,                substituted C₃-C₉ heteroaryl

    -   R4 is selected from the group consisting of C₆-C₁₀ aryl,        substituted C₆-C₁₀ aryl, C₃-C₉ heteroaryl, substituted C₃-C₉        heteroaryl, C₃-C₆ heterocyclyl, substituted C₃-C₆ heterocyclyl,        C₃-C₆ cycloalkyl, and substituted C₃-C₆ cycloalkyl;

    -   R5 is selected from the group consisting of hydrogen, F, Cl, CN,        —CH₃, —C₂H₅, —C₃H₇, and —CF₃;

    -   A is absent or —CH₂—

    -   and tautomers and pharmaceutically acceptable acid addition        salts thereof, and polymorphic forms thereof, provided that the        compound is not        2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-(4-methylpyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[1-[(6-methoxy-2-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3S,4S)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3R,4R)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3S,4S)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        2-[(3R,4R)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        4-[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]benzonitrile;        2-[(3S,4S)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;        2-[(3R,4R)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        or        2-[4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.

In a further embodiment (E2) of (E1) the one or more heteroaryls of R4,R8 and R10 independently of each other comprise one or two nitrogen.

In a further embodiment (E3) of (E1)) R8 is C₁-C₃ alkyl.

In a further embodiment (E4) of (E1)) R8 is branched C₁-C₃ alkyl.

In a further embodiment (E5) of (E1) R8 is phenyl or napthyl.

In a further embodiment (E6) of (E1) R8 is substituted phenyl orsubstituted napthyl.

In a particular embodiment (E7) of any of embodiments (E1) and E(6) thesubstituent is selected from the group consisting of F, Cl, methyl,trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino,cyclopropyl, and isopropyl.

In a particular embodiment (E8) of (E7) the substituents are selectedfrom the group consisting of F, Cl, methyl, trifluoromethyl, methoxy,trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E9) of any of embodiments (E1) and (E2) R8 is a C₄-C₉heteroaryl.

In a particular embodiment (E10) of embodiment (E9) R8 is selected fromthe group consisting of pyridyl, pyridazine, pyrimidinyl, pyrazinyl,quinolinyl, quinazolinyl, and quinoxalinyl.

In a further embodiment (E11) of any of embodiments (E1) and (E2) R8 isa substituted C₄-C₉ heteroaryl.

In a particular embodiment (E12) of embodiment (E11) R8 is selected fromthe group consisting of substituted pyridyl, substituted pyridazine,substituted pyrimidinyl, substituted pyrazinyl, substituted quinolinyl,and substituted quinazolinyl, and substituted quinoxalinyl.

In a particular embodiment (E13) of embodiment (E10) R8 is selected fromthe group consisting of 2-pyridyl, 3-pyridyl, 2-pyridazine,2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 2-quinoxalinyl,6-quinoxalinyl, and 2-quinazolinyl.

In a particular embodiment (E14) embodiment (E12) R8 is selected fromthe group consisting of substituted 2-pyridyl, substituted 3-pyridyl,substituted 2-pyridazine, substituted 2-pyrimidinyl, substituted4-pyrimidinyl, substituted 2-pyrazinyl, substituted 2-quinolinyl,substituted 2-quinoxalinyl, substituted 6-quinoxalinyl, and substituted2-quinazolinyl.

In a particular embodiment (E15) of any of embodiments (E1), (E2),(E11), (E12) and (E14) the substituent of R8 is selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particularthe substituents are selected from the group consisting of F, Cl,methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, anddimethylamino.

In an embodiment (E16) of embodiment (E1) R8 is C₁-C₄ alkoxy.

In a particular embodiment (E17) of (E16) R8 is methoxy or ethoxy.

In an embodiment (E18) of embodiment (E1) R8 is branched C₃-C₄ alkoxy.

In a particular embodiment (E19) of (E18) R8 is isopropoxy or isobutoxy.

In an embodiment (E20) of (E1), when R8 is C₆-C₁₀ aryloxy, R8 isselected from the group consisting of phenyloxy and naphthyloxy.

In an embodiment (E21) of (E1), when R8 is substituted C₆-C₁₀ aryloxy,R8 is selected from the group consisting of substituted phenyloxy andsubstituted naphthyloxy.

In a particular embodiment (E22) of any of embodiments (E1) and (E21)the substituents of R8, when R8 is a substituted C₆-C₁₀ aryloxy, isselected from the group consisting of F, Cl, methyl, trifluoromethyl,methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, andisopropyl; in particular the substituents are selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, and dimethylamino.

In an embodiment (E23) of any of embodiments (E1) and (E2) R8 is a C₄-C₉heteroaryloxy.

In an embodiment (E24) of embodiment (E23) R8 is selected from the groupconsisting of pyridineoxy, pyridazineoxy, pyrimidineoxy andquinoxalineoxy

In an embodiment (E25) of any of embodiments (E1) and (E2) R8 is asubstituted C₄-C₉ heteroaryloxy.

In an embodiment (E26) of embodiment (E25) R8 is selected from the groupconsisting of substituted pyridineoxy, pyridazineoxy, substitutedpyrimidineoxy and quinoxalineoxy

In an embodiment (E27) of any of embodiments (E1), (E2), (E25) and (E26)the substituent is selected from the group consisting of F, Cl, methyl,trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino,cyclopropyl, and isopropyl; in particular the substituents are selectedfrom the group consisting of F, Cl, methyl, trifluoromethyl, methoxy,trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E28) of embodiment (E1) R10 is a C₆-C₁₀ aryl selectedfrom the group consisting of phenyl and naphthyl.

In a preferred embodiment (E29) of embodiment (E28) R10 is phenyl.

In an embodiment (E30) of embodiment (E1) R10 is a substituted C₆-C₁₀aryl selected from the group consisting of substituted phenyl andsubstituted naphthyl.

In a preferred embodiment (E31) of embodiment (E28) R10 is substitutedphenyl.

In an embodiment (E32) of any of embodiments (E1), E(30) and E(31) thesubstituent is selected from the group consisting of F, Cl, methyl,trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino,cyclopropyl, and isopropyl; in particular the substituents are selectedfrom the group consisting of F, Cl, methyl, trifluoromethyl, methoxy,trifluoromethoxy, cyano, ethyl, and dimethylamino.

In an embodiment (E33) of any of embodiments (E1) and (E2) R10 is aC₄-C₉ heteroaryl.

In a particular embodiment (E34) of embodiment (E33) R10 is selectedfrom the group consisting of pyridyl, pyridazine, pyrimidinyl,pyrazinyl, quinolinyl, quinazolinyl, and quinoxalinyl.

In a particular embodiment (E35) of embodiment (E34) R10 is selectedfrom the group consisting of 2-pyridyl, 3-pyridyl, 2-pyridazine,2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl, 2-quinolinyl, 2-quinoxalinyl,6-quinoxalinyl, and 2-quinazolinyl.

In a further embodiment (E36) of any of embodiments (E1) and (E2) R10 isa substituted C₄-C₉ heteroaryl.

In a particular embodiment (E37) of embodiment (E36) R10 is selectedfrom the group consisting of substituted pyridyl, substitutedpyridazine, substituted pyrimidinyl, substituted pyrazinyl, substitutedquinolinyl, and substituted quinazolinyl, and substituted quinoxalinyl.

In a particular embodiment (E38) of embodiment (E37) R10 is selectedfrom the group consisting of substituted 2-pyridyl, substituted3-pyridyl, substituted 2-pyridazine, substituted 2-pyrimidinyl,substituted 4-pyrimidinyl, substituted 2-pyrazinyl, substituted2-quinolinyl, substituted 2-quinoxalinyl, substituted 6-quinoxalinyl,and substituted 2-quinazolinyl.

In a particular embodiment (E39) of any of embodiments (E1), (E2),(E36), (E37) and (E38) the substituent of R10 is selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, dimethylamino, cyclopropyl, and isopropyl; in particularthe substituents are selected from the group consisting of F, Cl,methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, ethyl, anddimethylamino.

In an embodiment (E40) of embodiment of embodiment (E1) R4 is selectedfrom the group consisting of phenyl and naphthyl.

In an embodiment (E41) of embodiment (E1) R4 is substituted phenyl.

In an embodiment (E42) of embodiment (E41) the substituent is selectedfrom the group consisting of F, Cl, methyl, trifluoromethyl, methoxy,trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, andisopropyl; in particular the substituents are selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, and dimethylamino.

In an embodiment (E43) of embodiment of embodiment (E1) R4 is pyridyl.

In an embodiment (E44) of embodiment (E1) R4 is substituted pyridyl.

In an embodiment (E45) of embodiment (E44) the substituent is selectedfrom the group consisting of F, Cl, methyl, trifluoromethyl, methoxy,trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, andisopropyl; in particular the substituents are selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, and dimethylamino.

In an embodiment (E46) of embodiment (E1) R4 is selected from the groupconsisting of tetrahydropyranyl, tetrahydrofuranyl and piperidyl.

In an embodiment (E47) of embodiment (E1) R4 is selected from the groupconsisting of substituted tetrahydropyranyl, substitutedtetrahydrofuranyl and substituted piperidyl.

In a particular embodiment (E48) of embodiment E(47) the substituent isselected from group consisting of F, Cl, methyl, cyano and methoxy.

In an embodiment (E49) of embodiment (E1) R4 is selected from the groupconsisting of cyclobutyl, cyclopentyl and cyclohexyl.

In a preferred embodiment (E50) of embodiment (E49) R4 is cyclopentyl orcyclohexyl.

In an embodiment (E51) of embodiment (E1) R4 is selected from the groupconsisting of substituted cyclobutyl, substituted cyclopentyl andsubstituted cyclohexyl.

In a preferred embodiment (E52) of embodiment (E51) R4 is substitutedcyclopentyl or substituted cyclohexyl.

In an embodiment (E53) of any of embodiments (E51) and (E52) substituentis selected from the group consisting of F, Cl, methyl, trifluoromethyl,methoxy, trifluoromethoxy, cyano, ethyl, dimethylamino, cyclopropyl, andisopropyl; in particular the substituents are selected from the groupconsisting of F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy,cyano, ethyl, and dimethylamino.

In an embodiment (E54) of embodiment (E1), the compound of formula (I)is selected among the compounds listed in Table 1, in the form of thefree base, one or more tautomers thereof or a pharmaceuticallyacceptable acid addition salt thereof.

In an embodiment (E55) of any of embodiments (E1) to (E54) the compoundhas an IC50 value, determined as described in the section “PDE9inhibition assay”, of 1 micro molar or less.

In an embodiment (E56) of embodiment (E1) the compound is selected fromthe compounds listed in Table 1.

In an embodiment (E57) of any of embodiments (E1) to (E56) the compoundis for use as a medicament.

In an embodiment (E58) of any of embodiments (E1) to (E56) the compoundis for use in the treatment of a disease selected from the groupconsisting of Alzheimer's disease, mental retardation; CIAS,attention-deficit/hyperactivity disorder; and age-related cognitivedecline, substance-induced psychotic disorder, for example psychosisinduced by alcohol, amphetamine, cannabis, cocaine, hallucinogens,inhalants, opioids, or phencyclidine.

In an embodiment (E59) of any of embodiments (E1) to (E56) the compoundis for preparation of a medicament for use in the treatment of a diseaseselected from the group consisting of Alzheimer's disease, mentalretardation; CIAS, attention-deficit/hyperactivity disorder; andage-related cognitive decline, substance-induced psychotic disorder, forexample psychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, or phencyclidine.

Embodiment (E60) of the present invention covers a method of treating asubject suffering from a disease selected from the group consisting ofAlzheimer's disease, mental retardation; CIAS,attention-deficit/hyperactivity disorder; and age-related cognitivedecline, substance-induced psychotic disorder, for example psychosisinduced by alcohol, amphetamine, cannabis, cocaine, hallucinogens,inhalants, opioids, or phencyclidine, which method comprisesadministering to said subject a compound of any of embodiments(E1)-(E56).

In an embodiment (E61) the present invention covers a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof any of embodiments (E1) to (E56), and one or more pharmaceuticallyacceptable carriers, diluents and excipients.

In an embodiment (E62) of embodiment (E61) the pharmaceuticalcomposition is for the treatment of a disease selected from the groupconsisting of Alzheimer's disease, mental retardation; CIAS,attention-deficit/hyperactivity disorder; and age-related cognitivedecline, substance-induced psychotic disorder, for example psychosisinduced by alcohol, amphetamine, cannabis, cocaine, hallucinogens,inhalants, opioids, or phencyclidine.

Table 1 lists compounds of the invention and the corresponding IC50values (nM) determined as described in the section “PDE9 inhibitionassay”. Each of the compounds constitutes an individual embodiment ofthe present invention:

TABLE 1 Compounds of the invention and IC50 values Compound PDE9_IC50(nM) 7-(4-fluorophenyl)-2-[4-methyl-1-[[6- 86(trifluoromethyl)-3-pyridyl]methyl]pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl- 67pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1-[[4- 12(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6- 281dihydro-2H-pyran-4-yl)-3H-imidazo[5,1- f][1,2,4]triazin-4-one7-(4-fluorophenyl)-2-[1-[(6-methoxy-3- 372pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3- 656pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(2,4-difluorophenyl)methyl]-4-methyl- 48pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(2,4- 201difluorophenyl)-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[4-methyl-1-[[4- 19 (trifluoromethoxy)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]- 3277-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(2-chloro-4-methoxy-phenyl)methyl]-4- 41methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1-(quinoxalin-6- 24ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-7- 563tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(4-methoxyphenyl)methyl]-4-methyl- 49pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[4-methyl-1-(4-pyridylmethyl)pyrrolidin-3- 52yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-(4-fluorophenoxy)azetidin-1-yl]methyl]- 807-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[4-methyl-1-(pyrimidin-5- 135ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[[4-(diethylamino)phenyl]methyl]-4- 13methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-(2-furylmethyl)-4-methyl-pyrrolidin-3-yl]- 257-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one7-(4-fluorophenyl)-2-[(3S,4S)-4-methyl-1- 341(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(2-chloro-4-fluoro-phenyl)methyl]-4- 21methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(4-dimethylaminophenyl)methyl]-4- 27methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[4-methyl-1-(p-tolylmethyl)pyrrolidin-3-yl]-7- 47tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-(benzyloxymethyl)-7-tetrahydropyran-4-yl- 3843H-imidazo[5,1-f][1,2,4]triazin-4-one2-[[3-(2,6-difluorophenoxy)azetidin-1- 155yl]methyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[1-(cyclohexylmethyl)-4-methyl-pyrrolidin- 4093-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one7-tetrahydropyran-4-yl-2-[[3-[4- 158(trifluoromethoxy)phenoxy]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4- one2-[[3-(4-dimethylaminophenyl)azetidin-1- 86yl]methyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[4-methyl-1-(3-pyridylmethyl)pyrrolidin-3- 37yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(2,6-difluorophenyl)methyl]-4-methyl- 62pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[(3-phenoxyazetidin-1-yl)methyl]-7-153 tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-[(4-fluorophenyl)methoxy]azetidin-1- 10yl]methyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]- 477-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[4-methyl-1-[(5-methyl-2- 28 furyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(5-chloro-2-furyl)methyl]-4-methyl- 63pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-7- 128tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[(3-phenylazetidin-1-yl)methyl]-7- 208tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-(4-methylphenoxy)azetidin-1-yl]methyl]- 917-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(5-fluoro-3-pyridyl)methyl]-4-methyl- 25pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[[3-(4-isopropylphenoxy)azetidin-1-134 yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(3,4-difluorophenyl)methyl]-4-methyl- 23pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(4-chlorophenyl)methyl]-4-methyl- 32pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[[6-(dimethylamino)-3-pyridyl]methyl]-4- 36methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one methyl 5-[[3-methyl-4-(4-oxo-7-8 tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1- yl]methyl]thiophene-2-carboxylate7-tetrahydropyran-4-yl-2-[[3-[5- 560(trifluoromethyl)-2-pyridyl]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4- one2-[[3-(3-pyridyloxy)azetidin-1-yl]methyl]-7- 350tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[(3R,4R)-1-[(2,4-difluorophenyl)methyl]-4- 47methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[(1R)-1-[3-(4-methoxyphenyl)azetidin-1- 22yl]ethyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-fluorophenoxy)azetidin-1-yl]ethyl]- 577-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[4-methyl-1-[(5-methyl-2- 22 thienyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(5-chloro-2-thienyl)methyl]-4-methyl- 13pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-[4-methyl-1-[(4-pyrrolidin-1- 61ylphenyl)methyl]pyrrolidin-3-yl]-7- tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one 2-(1-benzyl-4-methoxy-pyrrolidin-3-yl)-7- 54tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[4-methyl-1-(pyrimidin-4- Not determinedylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-hydroxyphenyl)azetidin-1-yl]ethyl]- 1207-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[(4-fluorophenyl)methyl]-4-methoxy- 94pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[4-methoxy-1-(p-tolylmethyl)pyrrolidin-3-yl]- 907-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-(p-tolylmethoxy)azetidin-1-yl]methyl]-7- 150tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[(3-benzylazetidin-1-yl)methyl]-7- Not determinedtetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[(3S,4S)-1-benzyl-4-methoxy-pyrrolidin-3- Not determinedyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[3-(4-methylphenoxy)azetidin-1-yl]ethyl]- 1107-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-[(4-methoxyphenoxy)methyl]azetidin-1- 82yl]methyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[(3-pyrimidin-2-ylazetidin-1-yl)methyl]-7- 3400tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1- 110yl]ethyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[1-benzyl-4-(trifluoromethyl)pyrrolidin-3-yl]- 507-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-(5-pyrrolidin-1-ylpyrimidin-2-yl)azetidin- 1201-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-dimethylaminophenyl)azetidin-1- 86yl]ethyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[4-methoxy-1-[(4- 83 methoxyphenyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-(3-phenylazetidin-1-yl)ethyl]-7- 360tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[3-(3-fluoro-4-methoxy-phenyl)azetidin- 2401-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(2-fluoro-4-methoxy-phenyl)azetidin- 3001-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-ethoxyphenyl)azetidin-1-yl]ethyl]-7- 290tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[3-[(4-methoxyphenyl)methyl]azetidin-1- 68yl]ethyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one7-tetrahydropyran-4-yl-2-[1-[3-[4- 210(trifluoromethoxy)phenyl]azetidin-1-yl]ethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[3-(4-methylphenoxy)azetidin-1-yl]ethyl]- 1107-tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[[3-[(4-methoxyphenoxy)methyl]azetidin-1- 82yl]methyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one2-[(3-pyrimidin-2-ylazetidin-1-yl)methyl]-7- 3400tetrahydropyran-4-yl-3H-imidazo[5,1- f][1,2,4]triazin-4-one2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1- 110yl]ethyl]-7-tetrahydropyran-4-yl-3H- imidazo[5,1-f][1,2,4]triazin-4-one

Definition of Substituents

As used in the context of the present invention, the terms “halo” and“halogen” are used inter-changeably and refer to fluorine, chlorine,bromine or iodine.

The term “C₁-C₆ alkyl” refers to a straight-chain or branched saturatedhydrocarbon having from one to six carbon atoms, inclusive. Examples ofsuch groups include, but are not limited to, methyl, ethyl, 1-propyl,2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, andn-hexyl. The expression “C1-C6 hydroxyalkyl” refers to a C₁-C₆ alkylgroup as defined above which is substituted with one hydroxy group.

The term “halo(C₁-C₆)alkyl” refers to a C₁-C₆ alkyl group as definedabove which is substituted with up to three halogen atoms, such astrifluoromethyl.

The expression “C₁-C₆ alkoxy” refers to a straight-chain or branchedsaturated alkoxy group having from one to six carbon atoms, inclusive,with the open valency on the oxygen. Examples of such groups include,but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy andn-hexyloxy.

The term “C₃-C₈ cycloalkyl” typically refers to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The expression “C₁-C₆ alkyl(C₃-C₈)cycloalkyl” refers to a C₃-C₈cycloalkyl as defined above which is substituted with a straight-chainor branched C₁-C₆ alkyl. Examples of such groups include, but are notlimited to, cyclopropylmethyl.

The term “heterocycloalkyl” refers to a four to eight membered ringcontaining carbon atoms and up to three N, O or S atoms, provided thatthe four to eight membered ring does not contain adjacent O or adjacentS atoms. The open valency is on either the heteroatom or carbon atom.Examples of such groups include, but are not limited to, azetidinyl,oxetanyl, piperazinyl, morpholinyl, thiomorpholinyl and [1,4]diazepanyl.

The term “hydroxyheterocycloalkyl” refers to a heterocycloalkyl asdefined above which is substituted with one hydroxy group.

The term “C₁-C₆ alkyl-heterocycloalkyl” refers to a heterocycloalkyl asdefined above which is substituted with a C₁-C₆ alkyl group. Examples ofsuch groups include, but are not limited to, tetrahydropyran-4-yl-methyland 2-morpholin-4-yl-ethyl.

The term “aryl” refers to a phenyl ring, optionally substituted withhalogen, C₁-C₆ alkyl, C₁-C₆ alkoxy or halo(C₁-C₈)alkyl as defined above.Examples of such groups include, but are not limited to, phenyl and4-chlorophenyl.

The term “C₁-C₆arylalkyl” refers to an aryl as defined above which issubstituted with a straight-chain or branched C₁-C₆ alkyl. Examples ofsuch groups include, but are not limited to, benzyl and 4-chlorobenzyl.

The term aryloxy refers to an univalent radical of the form Ar—O (suchas phenoxy) composed of an aryl group (Ar) united with oxygen (O).

The term heteroaryloxy refers to an aryloxy where one or more carbonatoms have been substituted with one more hetero atoms, such as N, O, S.

In the context of the present invention the term ‘cyclization point’ isunderstood to mean that connecting the atoms indicated to be cyclizationpoints by a bond results in a cyclic structure (a ring). The cyclizationpoint is indicated with a * in the illustrative reaction scheme below:

Additionally, the present invention further provides certain embodimentsof the invention, which are described below. Additionally, the presentinvention further provides certain embodiments of the invention that aredescribed below.

Pharmaceutically Acceptable Salts

The present invention also comprises salts of the compounds, typically,pharmaceutically acceptable salts. Such salts include pharmaceuticallyacceptable acid addition salts. Acid addition salts include salts ofinorganic acids as well as organic acids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines, forexample 8-bromotheophylline and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Berge, S. M. etal., J. Pharm. Sci. 1977, 66, 2, the contents of which are herebyincorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Pharmaceutical Composition

The present invention further provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula(I) and a pharmaceutically acceptable carrier or diluent. The presentinvention also provides a pharmaceutical composition comprising atherapeutically effective amount of one of the specific compoundsdisclosed in the Experimental Section herein and a pharmaceuticallyacceptable carrier or diluent.

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers, diluents orexcipients, in either single or multiple doses. The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable carriers or diluents as well as any otherknown adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)routes. It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, the compositions may be prepared withcoatings such as enteric coatings or they may be formulated so as toprovide controlled release of the active ingredient such as sustained orprolonged release according to methods well known in the art. Liquiddosage forms for oral administration include solutions, emulsions,suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Othersuitable administration forms include, but are not limited to,suppositories, sprays, ointments, creams, gels, inhalants, dermalpatches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg bodyweight per day. Typical oral dosages also range from about 0.01 to about50 mg/kg body weight per day. Typical oral dosages further range fromabout 0.05 to about 10 mg/kg body weight per day. Oral dosages areusually administered in one or more dosages, typically, one to threedosages per day. The exact dosage will depend upon the frequency andmode of administration, the sex, age, weight and general condition ofthe subject treated, the nature and severity of the condition treatedand any concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may also be presented in a unit dosage form by methodsknown to those skilled in the art. For illustrative purposes, a typicalunit dosage form for oral administration may contain from about 0.01 toabout 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg toabout 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscularand similar administration, typical doses are in the order of half thedose employed for oral administration.

The present invention also provides a process for making apharmaceutical composition comprising admixing a therapeuticallyeffective amount of a compound of formula (I) and at least onepharmaceutically acceptable carrier or diluent. In an embodiment, of thepresent invention, the compound utilized in the aforementioned processis one of the specific compounds disclosed in the Experimental Sectionherein.

The compounds of this invention are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. One exampleis an acid addition salt of a compound having the utility of a freebase. When a compound of formula (I) contains a free base such salts areprepared in a conventional manner by treating a solution or suspensionof a free base of formula (I) with a molar equivalent of apharmaceutically acceptable acid. Representative examples of suitableorganic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula (I)in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin Eor sesame or peanut oil may be employed. Such aqueous solutions shouldbe suitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The compounds of formula (I) may bereadily incorporated into known sterile aqueous media using standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents.Examples of solid carriers include lactose, terra alba, sucrose,cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and lower alkyl ethers of cellulose. Examples of liquidcarriers include, but are not limited to, syrup, peanut oil, olive oil,phospholipids, fatty acids, fatty acid amines, polyoxyethylene andwater.

Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax. The pharmaceutical compositionsformed by combining the compounds of formula (I) and a pharmaceuticallyacceptable carrier are then readily administered in a variety of dosageforms suitable for the disclosed routes of administration. Theformulations may conveniently be presented in unit dosage form bymethods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, andoptionally a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it may be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will range from about 25 mg to about 1 gper dosage unit. If a liquid carrier is used, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule or sterileinjectable liquid such as an aqueous or non-aqueous liquid suspension orsolution.

The pharmaceutical compositions of the invention may be prepared byconventional methods in the art. For example, tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tablettingmachine prepare tablets. Examples of adjuvants or diluents comprise:corn starch, potato starch, talcum, magnesium stearate, gelatin,lactose, gums, and the like. Any other adjuvants or additives usuallyused for such purposes such as colorings, flavorings, preservatives etc.may be used provided that they are compatible with the activeingredients.

Diseases

In a particular embodiment the PDE9 inhibitors of the present inventionmay be used in the treatment of cognition deficiencies related toneurodegenerative disorders, such dementia, such as cortical dementia orsubcortical dementia.

Cortical dementias arise from a disorder affecting the cerebral cortex,the outer layers of the brain that play a critical role in cognitiveprocesses such as memory and language. Particularly considered corticaldementias are Alzheimer's disease; vascular dementia (also known asmulti-infarct dementia), including Binswanger's disease; Dementia withLewy bodies (DLB); Alcohol-Induced Persisting Dementia, includingKorsakoff's syndrome and Wernicke's encephalopathy; frontotemporal lobardegeneration (FTLD), including: Pick's disease, frontotemporal dementia(or frontal variant FTLD), semantic dementia (or temporal variant FTLD),and progressive non-fluent aphasia; Creutzfeldt-Jakob disease; dementiapugilistica; Moyamoya disease; and posterior cortical atrophy (anAlzheimer's disease variant).

Subcortical dementias result from dysfunction in the parts of the brainthat are beneath the cortex. Usually, the memory loss and languagedifficulties that are characteristic of cortical dementias are notpresent. Rather, people with subcortical dementias, such as Huntington'sdisease, Parkinson's Disease, and AIDS dementia complex, tend to showchanges in their personality and attention span, and their thinkingslows down. Particularly considered subcortical dementias are dementiadue to Huntington's disease, dementia due to hypothyroidism, dementiadue to Parkinson's disease, dementia due to Vitamin B1 deficiency,dementia due to Vitamin B12 deficiency, dementia due to folatedeficiency, dementia due to syphilis, dementia due to subdural hematoma,dementia due to hypercalcaemia, dementia due to hypoglycaemia, AIDSdementia complex, pseudodementia (a major depressive episode withprominent cognitive symptoms), substance-induced persisting dementia,dementia due to multiple etiologies, dementia due to other generalmedical conditions (i.e. end stage renal failure, cardiovascular diseaseetc.), dementia not otherwise specified (used in cases where no specificcriteria is met).

EXPERIMENTAL General Description of pyrrolidine-substituted3H-imidazo[5,1-f][1,2,4]triazin-4-ones

Compounds of formula I can be made by reductive amination of compoundsof formula X, with aryl aldehydes in the presence of NaBH₃CN orNa(OAc)₃BH, and a few drops of acetic acid as catalyst in DME or MeOH,or by alkylation of compound X with aryl methyl halides, in the presenceof bases, such as K₂CO₃ or DIEA, in DMF or CH₃CN.

Compounds of formula X can be prepared by deprotection with HCl in MeOHof compound of formula IX, which can be obtained by one-pothydrogenolysis debenzylation and Boc protection with Boc₂O of compoundswith formula VIII. Compounds of formula VIII can be synthesized bySuzuki reaction of compounds of formula VII, with a variety of organoboronic acids or boronic esters in the presence of Xantphos, and apalladium catalyst, such as Pd(dppf)Cl₂, Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄ and abase, such as K₃PO₄, K₂CO₃, or Cs₂CO₃, with conventional heating ormicrowave heating in DMF or Toluene. Compounds of formula VII can beprepared by deprotonation with n-BuLi, followed by treatment with I₂, ofcompound VI, which can be made by cyclization in the presence of NH₄OAcin MeOH with heating of compound V. Compound V can be made by couplingreaction of compound III, obtained from reaction between compound IIwith (aminooxy)diphenylphosphine oxide, with compound IV, which can beprepared from a known compound XI. Compound XI is made according to theprocedures in patent WO 2009/76387.

General Description of Azetidine-substituted3H-imidazo[5,1-f][1,2,4]triazin-4-ones

Compounds of formula XI, when R is proton, can be made from directdisplacement of a chloride of formula X, with different amines in thepresence of a base, such as DIEA. Compounds of formula X can begenerated from the reaction between compounds of formula IX with thionylchloride. Compounds of formula XI, when R is an alkyl group, can besynthesized from reductive amination of ketones of formula XII with avariety of amines, in the presence of Na(CN)BH₃ or Na(OAc)₃BH. Ketonesof formula XII can be made from oxidation of the alcohol of formula IXwith MnO₂ in DCM.

Alcohols of formula IX can be prepared from debenzylation, with Pd/C in50 psi of H₂, of compounds of formula VIII, which can be synthesized bySuzuki coupling of compounds of formula VII, with a variety of boronicacids or boronic esters, in the presence of a palladium catalyst, suchas Pd(PPh₃)₄, Pd(dppf)CL₂, etc, with microwave heating. Compounds offormula VII can be generated from deprotonation of compounds of formulaVI with a base, such as n-BuLi, followed by treatment with I₂.

Compounds of formula VI can be made from microwave heating of amide offormula V in the presence of aqueous solution of a base, such as KOH.Amide of formula V can be generated from aminolysis of esters of formulaIV with aqueous solution of ammonia. Esters of formula IV can beprepared by coupling in the presence of HATU of carboxylic acid III with1-amino-imidazole II, which was made from the reaction of methyl1H-imidazole-5-carboxylate (1) with (aminooxy)diphenylphosphine oxide inthe presence of a base, such as LiHMDS.

Part I (Pyrrolidine Series) Preparation of Intermediates2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one

3-Amino-3H-imidazole-4-carboxylic acid methyl ester (2)

To a suspension of compound 1 (4.0 g, 31.7 mmol) in dry THF was dropwiseadded LiHMDS (38 mL, 38 mmol) at −78° C. in N₂. The mixture was stirredat −78° C. for 2 hours. Then it was stirred at −30° C. for 20 minutes.(Aminooxy)diphenylphosphine oxide (8.14 g, 31.7 mmol) was added inportions at −10° C. The reaction mixture was allowed to warm to r.tovernight. The reaction mixture was diluted with EtOAc (100 mL) andfiltered. The filtrate was concentrated in vacuum. The residue waspurified by silica gel column chromatography (eluted with DCM/MeOH=150:1to 100:1) to afford the desired product 2 (2.4 g, 53% yield) as a whitepowder. LC-MS: m/z 142.50 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 7.82 (s,1H), 7.54 (s, 1H), 6.20 (br. s, 2H), 3.79 (s, 3H).

3-[(1-Benzyl-4-methyl-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylicacid methyl ester (4)

A mixture of compound 3 (prepared according to procedures in patent WO2009/76387) (13 g, 59.4 mmol) in 30 mL of SOCl₂ was refluxed at 85° C.for 4 hours. The solvent was removed by concentration in vacuo to affordthe acid chloride of 3.

The acid chloride was dissolved in 30 mL of CH₂Cl₂. This resultingsolution was added dropwise to a solution of compound 2 (3.5 g, 24.8mmol) and Et₃N (10 mL, 68.2 mmol) in 100 mL of CH₂Cl₂ at 0° C. over 20minutes. Then the reaction mixture was stirred at room temperature for 8hours. The reaction mixture was washed with brine (100 mL×2). Theorganic phase was dried over Na₂SO₄, filtered and concentrated to affordthe crude residue, which was purified by column chromatography on silicagel (eluted with DCM/MeOH=100:1 to 50:1) to afford compound 4 (5.0 g,58.9% yield) as a red oil. LC-MS: m/z 343.11 [M+1]⁺. ¹H NMR (400 MHz,CDCl₃): δ 7.70 (s, 1H), 7.63 (s, 1H), 7.33˜7.25 (m, 5H), 3.78 (s, 3H),3.80˜3.77 (d, J=12.4 Hz, 1H), 3.68˜3.65 (d, J=12.4 Hz, 1H), 3.36˜3.28(m, 2H), 2.70˜2.65 (m, 1H), 2.56˜2.50 (m, 2H), 1.92 (m, 1H), 1.16 (d,J=7.2 Hz, 3H).

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(5)

To a 300 mL sealed tube was added a mixture of compound 4 (4.7 g, 13.7mmol), NH₄OAc (11 g, 14.3 mmol) and ammonium hydroxide (50 mL) in MeOH(120 mL). The reaction mixture was stirred at 130° C. for 2 days. Aftercooling down, the reaction mixture was concentrated in vacuo. Theresidue was diluted with CH₂Cl₂ (100 mL) and washed with water (50mL×2). The organic phase was separated and dried over Na₂SO₄. Afterfiltering, the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluted withDCM/MeOH=50:1 to 30:1) to afford compound 5 (1.8 g, 40.6% yield) as awhite solid. LC-MS: m/z 310.17 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.02(s, 1H), 7.85 (s, 1H), 7.39˜7.28 (m, 5H), 3.82 (d, J=12.4 Hz, 1H), 3.58(d, J=12.4 Hz, 1H), 3.41˜3.37 (m, 1H), 2.99 (d, J=6.4 Hz, 1H), 2.72˜2.70(m, 1H), 2.54˜2.50 (m, 1H), 2.44˜2.40 (m, 1H), 1.95˜1.91 (m, 1H), 1.20(d, J=6.4 Hz, 3H).

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one(6)

To a solution of compound 5 (1.0 g, 3.24 mmol) in dry THF (70 mL) wasadded n-BuLi (2.5 M, 2 mL) dropwise at −78° C. over 30 minutes. Thereaction was stirred at −45° C. for 30 minutes. Then a solution ofiodine in THF (20 mL) was dropwise added at −78° C. over 10 minutes. Theresulting mixture was stirred at 0° C. for 2 hours. The reaction wasquenched with saturated aqueous Na₂S₂O₃ solution (10 mL). Then thereaction mixture was diluted with EtOAc (200 mL), and washed with brine(50 mL×2). The separated organic phase was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel (eluted by PE/EtOAc=10:1 to 2:1) toafford compound 6 (930 mg, 66% yield) as a white solid. LC-MS: m/z435.99 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (s, 1H), 7.37˜7.26 (m,5H), 3.82 (d, J=12.4 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H), 3.42˜3.38 (m,1H), 2.98 (d, J=8.4 Hz, 1H), 2.82˜2.81 (m, 1H), 2.55˜2.51 (m, 1H),2.45˜2.42 (m, 1H), 1.96˜1.92 (m, 1H), 1.22 (d, J=7.2 Hz, 3H).

2-(4-Methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(7)

To a mixture of compound 6 (100 mg, 0.23 mmol) and4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(145 mg, 0.69 mmol) in DMF (10 mL) was added potassium phosphate (146mg, dissolved in 1 mL of H₂O). The reaction mixture was degassed bypurging with N₂ for 15 min, before Pd(dppf)₂Cl₂ (28 mg, 0.035 mmol) andXantphos (40 mg, 0.069 mmol) were added. The resulting suspension wasbubbled with nitrogen for 10 minutes. The reaction mixture was heated to150° C. under microwave irradiation for one hour. After cooling down,the reaction mixture was diluted with EtOAc (50 mL), and the precipitatewas filtered off. The filtrate was washed with brine (50 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated. The crude productwas purified by column chromatography on silica gel (eluting with EtOAc)to afford 7 (50 mg, 55% yield) as a white solid. LC-MS: m/z 393.03[M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.85 (s, 1H), 7.37˜7.22 (m, 6H), 4.40(d, J=2.8 Hz, 2H), 3.95˜3.92 (m, 2H), 3.82˜3.79 (d, J=12.6 Hz, 1H),3.61˜3.58 (d, J=12.6 Hz, 1H), 3.39˜3.37 (m, 1H), 3.00˜2.98 (d, J=10.0Hz, 1H), 2.76˜2.73 (m, 3H), 2.54˜2.52 (m, 1H), 2.44˜2.42 (m, 1H),1.95˜1.90 (m, 2H), 1.21 (d, J=7.2 Hz, 3H).

3-Methyl-4-[4-oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (8)

To a 75 mL flask was added compound 7 (0.3 g, 0.76 mmol), di-tert-butyldicarbonate (1.6 g, 7.6 mmol), potassium acetate (0.75 g, 7.6 mmol), 10%Pd/C (300 mg, 0.28 mmol) and methanol (40 mL). The reaction mixture wasstirred with hydrogen (50 psi) at 50° C. until LC-MS showed that thestarting material was almost consumed. After cooling down, the reactionmixture was filtered through Celite. The filtrate was concentrated underreduced pressure. The crude product was purified by columnchromatography on silica gel (eluting with EtOAc) to afford compound 8(50 mg, 42% yield) as a white solid. LC-MS: m/z 404.35 [M+1]⁺. ¹H NMR(400 MHz, CDCl₃): δ 10.49 (br. s, 1H), 7.86 (s, 1H), 4.11˜4.08 (m, 2H),3.91 (m, 1H), 3.76 (m, 1H), 3.63˜3.57 (m, 3H), 3.46˜3.41 (m, 1H),3.11˜3.06 (m, 1H), 2.91˜2.89 (m, 1H), 2.69˜2.65 (m, 1H), 2.11˜2.05 (m,2H), 1.93˜1.90 (m, 2H), 1.48 (s, 9H), 1.20˜1.18 (d, J=6.8 Hz, 3H).

2-(4-Methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt (9)

To a solution of compound 8 (130 mg, 0.32 mmol) in CH₂Cl₂ (10 mL) wasadded a saturated solution of HCl in diethylether (20 mL). The resultingmixture was stirred at room temperature for 2 hours. The reaction wasconcentrated in vacuo to dryness to afford compound 9 (110 mg, 100%yield). LC-MS (free base): m/z 304.37 [M+1]⁺. ¹H NMR (400 MHz, D₂O-d2):δ 8.02 (s, 1H), 3.98˜3.95 (dd, J=2.8, 8.8 Hz, 2H), 3.64˜3.60 (m, 3H),3.56˜3.50 (m, 3H), 3.15˜3.09 (m, 1H), 3.01˜2.96 (m, 1H), 2.72˜2.67 (m,1H), 1.92˜1.87 (m, 4H), 1.09 (d, J=6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-(4-methyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-fluoro-phenyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(10)

To a solution of compound 6 (500 mg, 1.14 mmol) and4-fluorophenylboronic acid (300 mg, 2.14 mmol) in 30 mL of toluene wasadded K₂CO₃ (1.0 g, 7.24 mmol). The resulting mixture was degassed bypurging with nitrogen for 15 min, before Pd(PPh₃)₄ (120 mg, 0.10 mmol)was added. The resulting suspension was bubbled with nitrogen for 10minutes. The reaction mixture was heated to 100° C. for 18 hours andthen cooled to room temperature. After removal of the solvent, theresidue was purified by chromatography on silica gel column (eluted withPE/EtOAc=5:1 to 1:2) to afford compound 10 (398 mg, 86% yield) as awhite solid. LC-MS: m/z 404.31 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ8.34˜8.31 (m, 2H), 7.95 (s, 1H), 7.38 (m, 4H), 7.31 (m, 1H), 7.16 (m,2H), 3.85 (d, J=12.4 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.44˜3.40 (m,1H). 3.05 (d, J=10 Hz, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.50˜2.47 (m,1H), 1.99 (m, 1H), 1.22 (d, J=6.8 Hz, 3H).

3-[7-(4-Fluoro-phenyl)-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl]-4-methyl-pyrrolidine-1-carboxylicacid tert-butyl ester (11)

Compound 11 was prepared in the same method as described for preparationof compound 8. 46% yield. LC-MS: m/z 414.08 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d6): δ 12.01 (br. s, 1H), 8.36 (m, 2H), 7.88 (s, 1H), 7.35 (m, 2H),3.75 (m, 1H), 3.56 (m, 2H). 2.95 (m, 2H), 2.64 (m, 1H), 1.39 (s, 9H),1.10 (d, J=6.4 Hz, 3H).

7-(4-Fluoro-phenyl)-2-(4-methyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt (12)

Compound 12 was prepared in the same way as described for preparationfor compound 9. 95% yield. LC-MS: m/z 314.31 [M+1]⁺. ¹H NMR (400 MHz,DMSO-d6): δ 12.19 (s, 1H), 9.47˜9.49 (br. s, 2H), 8.37 (dd, J=5.6, 8.4Hz, 2H), 7.93 (s, 1H), 7.39 (m, 2H), 3.67 (m, 1H), 3.48 (m, 2H). 3.09(m, 1H), 2.91 (m, 1H), 2.71 (m, 1H), 1.15 (d, J=6.8 Hz, 3H).

3-[(1-Benzyl-4-trifluoromethyl-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylicacid methyl ester (13)

To a solution of compound 2 (2.0 g, 14.1 mmol),1-Benzyl-4-trifluoromethyl-pyrrolidine-3-carboxylic acid (4.06 g, 14.9mmol) and DIEA (10 mL, 42.5 mmol) in DMF (30 mL) was added HATU (8.1 g,21.2 mmol). The resulting reaction mixture was stirred at r.t.overnight. The reaction was monitored by LC-MS. The reaction wasquenched with water (100 mL) when it was complete. The aqueous solutionwas extracted with EtOAc (80 mL×3). The combined organic phase waswashed with brine and concentrated to afford the crude product. Theresidue was purified by silica gel column (eluted with PE/EA=5:1 to 1:2)to afford compound 13 (4.8 g, 85.6% yield) as white oil. LC-MS: m/z 397[M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.00 (br. s, 1H), 7.70 (s, 1H), 7.65(s, 1H), 7.34˜7.28 (m, 5H), 3.81 (s, 3H), 3.78˜3.72 (m, 2H), 3.41˜3.38(m, 1H), 3.30˜3.24 (m, 2H), 3.14˜3.12 (m, 1H), 2.71˜2.67 (m, 1H),2.58˜2.53 (m, 1H).

2-(1-Benzyl-4-trifluoromethyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(14)

The procedure for the preparation of compound 14 was similar to that ofcompound 5.

28.8% yield. LC-MS: m/z 364 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.06 (s,1H), 7.88 (s, 1H), 7.41˜7.30 (m, 5H), 3.88 (d, J=12.8 Hz, 1H), 3.67 (d,J=12.4 Hz, 1H), 3.45˜3.40 (m, 1H), 3.35˜3.33 (m, 1H), 3.08˜3.06 (m, 2H),2.65˜2.61 (m, 1H), 2.52˜2.48 (m, 1H).

2-(1-Benzyl-4-trifluoromethyl-pyrrolidin-3-yl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one(15)

The procedure for the preparation of compound 15 was similar to that ofcompound 6.

38.7% yield. LC-MS: m/z 490 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.91 (s,1H), 7.40˜7.29 (m, 5H), 3.87 (d, J=12.8 Hz, 1H), 3.66 (d, J=12.4 Hz,1H), 3.46˜3.41 (m, 2H), 3.08˜3.05 (m, 2H), 2.67˜2.62 (m, 1H), 2.54˜2.49(m, 1H).

2-(1-Benzyl-4-trifluoromethyl-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(16)

The procedure for the preparation of compound 16 was similar to that ofcompound 7.

91% yield. LC-MS: m/z 446 [M+1]⁺. ¹HNMR (400 MHz, CDCl₃): δ 7.87 (s,1H), 7.37˜7.27 (m, 5H), 7.18 (m, 1H), 4.39 (m, 2H), 3.94˜3.91 (m, 2H),3.88˜3.85 (m, 1H), 3.68˜3.65 (m, 1H), 3.41˜3.36 (m, 2H), 3.09˜3.04 (m,2H), 2.76 (m, 2H), 2.65˜2.60 (m, 1H), 2.52˜2.47 (m, 1H).

3-[4-Oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl]-4-trifluoromethyl-pyrrolidine-1-carboxylicacid tert-butyl ester (17)

The procedure for the preparation of compound 17 was similar to that ofcompound 8.

27% yield. LC-MS: m/z 458 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.89 (s,1H), 4.13˜4.03 (m, 3H), 3.89˜3.87 (m, 1H), 3.68˜3.58 (m, 3H), 3.46˜3.39(m, 1H), 2.14˜2.05 (m, 2H), 1.92˜1.89 (m, 2H), 1.77˜1.59 (m, 3H), 1.47(s, 9H).

7-(Tetrahydro-pyran-4-yl)-2-(4-trifluoromethyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt (18)

The procedure for the preparation of compound 18 was similar to that ofcompound 9.

100% yield. LC-MS: m/z 358 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 7.90(br. s, 1H), 3.96˜3.93 (m, 3H), 3.75˜3.70 (m, 3H), 3.56˜3.50 (m, 5H),1.87˜1.82 (m, 4H).

3-[(1-Benzyl-4-methoxy-pyrrolidine-3-carbonyl)-amino]-3H-imidazole-4-carboxylicacid methyl ester (19)

The procedure for the preparation of compound 19 was similar to that ofcompound 4.

77% yield. LC-MS (ESI): m/z=359.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ7.70 (d, J=0.4 Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.33˜7.27 (m, 5H),4.22˜4.19 (m, 1H), 3.80 (s, 3H), 3.76 (d, J=6.8 Hz, 2H), 3.45˜3.41 (m,1H), 3.37 (s, 3H), 3.25˜3.22 (m, 1H), 2.98˜2.95 (m, 1H), 2.74˜2.69 (m,1H), 2.40˜2.37 (m, 1H).

2-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(20)

The procedure for the preparation of compound 20 was similar to that ofcompound 5.

32% yield. LC-MS (ESI): m/z=325.3 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ8.05 (s, 1H), 7.87 (s, 1H), 7.38˜7.30 (m, 5H), 4.00˜3.96 (m, 1H), 3.86(d, J=12.6 Hz, 1H), 3.62 (d, J=12.6 Hz, 1H), 3.57˜3.53 (m, 1H), 3.38 (s,3H), 3.14˜3.12 (m, 1H), 3.02˜2.99 (m, 1H), 2.74˜2.68 (m, 1H), 2.36˜2.31(m, 1H).

2-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one(21)

The procedure for the preparation of compound 21 was similar to that ofcompound 6.

38% yield. LC-MS (ESI): m/z=452.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ7.91 (s, 1H), 7.40˜7.30 (m, 5H), 4.00˜3.96 (m, 1H), 3.88˜3.84 (m, 1H),3.66˜3.49 (m, 2H), 3.40 (s, 3H), 3.24˜3.22 (m, 1H), 3.03˜2.99 (m, 1H),2.74˜2.69 (m, 1H), 2.37˜2.32 (m, 1H).

2-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(22)

The procedure for the preparation of compound 22 was similar to that ofcompound 7.

85% yield. LC-MS (ESI): m/z=408 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.91(s, 1H), 7.40˜7.29 (m, 5H), 7.21 (m, 1H), 4.39˜4.38 (m, 2H), 4.00˜3.97(m, 1H), 3.95˜3.92 (m, 2H), 3.87˜3.84 (m, 1H), 3.65˜3.62 (m, 1H),3.55˜3.49 (m, 2H), 3.40˜3.37 (s, 3H), 3.17˜3.14 (m, 1H), 3.03˜3.00 (m,1H), 2.78˜2.70 (m, 2H), 2.36˜2.32 (m, 1H).

3-Methoxy-4-[4-oxo-7-(tetrahydro-pyran-4-yl)-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl]-pyrrolidine-1-carboxylicacid tert-butyl ester (23)

The procedure for the preparation of compound 23 was similar to that ofcompound 8.

46% yield. LC-MS (ESI): m/z=420 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84(s, 1H), 4.10˜4.06 (m, 2H), 3.96˜3.80 (m, 2H), 3.61˜3.54 (m, 2H), 3.48(s, 3H), 3.42˜3.31 (m, 1H), 3.31˜3.22 (m, 2H), 2.09˜2.03 (m, 2H),2.02˜1.89 (m, 2H), 1.62˜1.58 (m, 2H), 1.49 (s, 9H).

2-(4-Methoxy-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneHydrochloric acid salt (24)

The procedure for the preparation of compound 24 was similar to that ofcompound 9.

100% yield. LC-MS (ESI): m/z=320.2 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ9.77˜9.62 (br. s, 2H), 7.88 (s, 1H), 4.40˜4.35 (m, 1H), 3.95˜3.91 (m,2H), 3.69˜3.49 (m, 6H), 3.36 (s, 3H), 1.85˜1.79 (m, 4H), 1.30˜1.23 (m,1H), 1.11˜1.05 (m, 1H).

Preparation of Target Compounds: Example 12-[1-(4-Fluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

To a solution of compound 9 (80 mg, 0.263 mmol) and 4-fluorobenzaldehyde(326 mg, 2.63 mmol) in 1,2-dichloroethane (15 mL) was added 2 drops ofacetic acid. The resulting solution was stirred at room temperature forone hour. Then NaBH₃CN (178 mg, 2.63 mmol) was added to the reaction inportions. The resulting mixture was stirred at room temperature for 16hours. LC-MS showed that the starting material was almost consumed. Thereaction mixture was quenched with water (40 mL), and extracted withCH₂Cl₂ (30 mL×3). The combined organic phases were washed with brine (30mL), and dried over Na₂SO₄. After filtered, the filtrate wasconcentrated in vacuum. The residue was purified by preparative TLC toafford the desired product (20 mg, 21% yield) as a white solid. LC-MS:m/z 412.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.27 (s, 1H), 7.61 (s,1H), 7.35˜7.31 (m, 2H), 7.02˜6.98 (m, 2H), 3.96˜3.93 (m, 2H), 3.79˜3.70(m, 2H), 3.51˜3.39 (m, 3H), 3.15˜3.11 (m, 1H), 3.05˜2.95 (m, 2H),2.84˜2.79 (m, 1H), 2.61˜2.57 (m, 1H), 2.33˜2.29 (m, 1H), 1.93˜1.87 (m,2H), 1.80˜1.77 (m, 2H), 1.09 (d, J=6.8 Hz, 3H).

The racemic mixture of2-[1-(4-Fluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-onewas submitted for preparative chiral HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=12 mL/min; UV: 230 nm; 30 mg/injin) and give two enantiomers:

2-((3S,4S)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=7.03. LC-MS: m/z412.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (s, 1H), 7.34˜7.31 (m,2H), 7.07˜7.03 (m, 2H), 4.11˜4.05 (m, 2H), 3.79˜3.76 (d, J=12.8 Hz, 1H),3.62˜3.53 (m, 3H), 3.41˜3.35 (m, 2H), 2.97˜2.95 (d, J=10.4 Hz, 1H),2.76˜2.74 (m, 1H), 2.52˜2.48 (m, 1H), 2.43˜2.41 (m, 1H), 2.10˜2.02 (m,2H), 1.93˜1.86 (m, 3H), 1.09 (d, J=6.8 Hz, 3H).

2-((3R,4R)-1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=9.03. LC-MS: m/z412.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (s, 1H), 7.33˜7.30 (m,2H), 7.06˜7.02 (m, 2H), 4.10˜4.05 (m, 2H), 3.78˜3.74 (d, J=12.8 Hz, 1H),3.60˜3.52 (m, 3H), 3.41˜3.36 (m, 2H), 2.98˜2.95 (d, J=10.0 Hz, 1H),2.76˜2.73 (m, 1H), 2.52˜2.49 (m, 1H), 2.43˜2.41 (m, 1H), 2.08˜2.01 (m,2H), 1.93˜1.85 (m, 3H), 1.09 (d, J=6.4 Hz, 3H).

The following compounds were prepared in a similar way:

7-(4-fluorophenyl)-2-(1-(4-methoxybenzyl)-4-methylpyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

42% yield. LC-MS: m/z 434.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ8.25˜8.22 (m, 2H), 7.78 (s, 1H), 7.23˜7.15 (m, 4H), 6.85˜6.82 (m, 2H),3.72 (s, 3H), 3.69 (m, 2H), 3.13 (m, 1H), 3.06˜3.02 (m, 1H), 2.98˜2.88(m, 1H), 2.86˜2.84 (m, 1H), 2.62˜2.59 (m, 1H), 2.30˜2.26 (m, 1H), 1.12(d, J=6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-[4-methyl-1-(6-trifluoromethyl-pyridin-3-ylmethyl)-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

29% yield. LC-MS: m/z 473.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.67 (br.s, 1H), 8.36˜8.32 (m, 2H), 8.00˜7.96 (m, 1H), 7.96 (s, 1H), 7.77˜7.75(d, J=8.0 Hz, 1H), 7.19˜7.15 (m, 2H), 3.87˜3.79 (m, 2H), 3.42˜3.48 (m,1H), 3.09˜3.06 (d, J=10.0 Hz, 1H), 2.90˜2.87 (m, 1H), 2.68˜2.64 (m, 1H),2.51˜2.49 (m, 1H), 2.01˜1.97 (dd, J=8.4, 9.2 Hz, 1H), 1.25 (d, J=6.8 Hz,3H).

2-[1-(6-Methoxy-pyridin-3-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

23% yield, LC-MS: m/z 425.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.22(br. s, 1H), 7.92 (s, 1H), 7.78 (dd, J=2.4, 8.4 Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 4.42˜4.27 (m, 2H), 3.96˜3.94 (m, 2H), 3.89 (s, 3H), 3.84˜3.81(m, 2H), 3.68˜3.64 (m, 2H), 3.64˜3.56 (m, 2H), 3.20 (m, 2H), 2.85˜2.82(m, 1H), 1.98˜1.85 (m, 4H), 1.18 (d, J=6.4 Hz, 3H).

2-[4-Methyl-1-(6-trifluoromethyl-pyridin-3-ylmethyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

18% yield, LC-MS: m/z 463.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.66 (s,1H), 7.98 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.76 (d, J=8.0 Hz, 1H),4.11˜4.06 (m, 2H), 3.87˜3.84 (d, J=13.2 Hz, 1H), 3.78˜3.74 (d, J=13.2Hz, 1H), 3.62˜3.54 (m, 2H), 3.36˜3.41 (m, 2H), 3.04˜3.02 (d, J=9.6 Hz,1H), 2.83˜2.81 (m, 1H), 2.63 (m, 1H), 2.54 (m, 1H), 2.11˜2.09 (m, 1H),2.07˜1.98 (m, 2H), 1.90˜1.88 (m, 2H), 1.25 (d, J=6.8 Hz, 3H).

2-[1-(6-Methoxy-pyridin-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

9% yield, LC-MS: m/z 425.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.59(s, 1H), 7.53˜7.51 (m, 1H), 6.89 (d, J=7.2 Hz, 1H), 6.58 (d, J=8.0 Hz,1H), 3.95˜3.92 (m, 2H), 3.82 (s, 3H), 3.73˜3.62 (m, 2H), 3.52˜3.46 (m,3H), 3.19˜3.15 (m, 1H), 3.05˜3.03 (m, 1H), 2.93˜2.91 (m, 1H), 2.78 (m,1H), 2.54 (m, 1H), 2.25˜2.23 (m, 1H), 1.92˜1.87 (m, 2H), 1.81˜1.78 (m,2H), 1.09 (d, J=6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-[1-(6-methoxy-pyridin-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

47% yield. LC-MS: m/z 435.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.29 (m,2H), 7.87 (s, 1H), 7.48 (m, 1H), 7.09 (m, 2H), 6.81 (m, 1H), 6.58 (m,1H), 3.91 (s, 3H), 3.85˜3.77 (m, 1H), 3.62˜3.59 (m, 1H), 3.42˜3.38 (m,1H), 3.07 (m, 1H), 2.77 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 1.95 (m,1H), 1.09 (d, J=6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-[1-(6-methoxy-pyridin-3-ylmethyl)-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

22% yield. LC-MS: m/z 435.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.36˜8.33(m, 2H), 8.07 (d, J=1.2 Hz, 1H), 7.95 (s, 1H), 7.68˜7.65 (dd, J=2.4, 8.4Hz, 1H), 7.18˜7.14 (m, 2H), 6.80 (d, J=8.4 Hz, 1H), 3.93 (s, 3H),3.74˜3.70 (d, J=12.8 Hz, 1H), 3.60˜3.57 (d, J=12.8 Hz, 1H), 3.40˜3.36(m, 1H), 3.05˜3.02 (d, J=10.4 Hz, 1H), 2.82 (m, 1H), 2.56 (m, 1H),1.95˜1.91 (m, 2H), 1.14 (d, J=6.8 Hz, 3H).

7-(4-Fluoro-phenyl)-2-(4-methyl-1-pyridin-2-ylmethyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

49% yield. LC-MS: m/z 405.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.44(d, J=4.4 Hz, 1H), 8.24˜8.22 (m, 2H), 7.77 (s, 1H), 7.73˜7.69 (m, 1H),7.41 (d, J=8.0 Hz, 1H), 7.24˜7.21 (m, 1H), 7.17˜7.12 (m, 2H), 3.84˜3.73(m, 2H), 3.12˜3.10 (m, 1H), 3.04˜3.00 (m, 1H), 2.94˜2.89 (m, 1H),2.85˜2.81 (m, 1H), 2.61˜2.59 (m, 1H), 2.26˜2.22 (t, J=8.4 Hz, 1H), 1.10(d, J=6.8 Hz, 3H).

2-[1-(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

88% yield. LC-MS: m/z 387.1 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.73(s, 1H), 7.52˜7.46 (m, 1H), 6.96˜7.01 (m, 2H), 4.08˜4.05 (m, 2H), 3.79(s, 2H), 3.65˜3.55 (m, 3H), 3.18˜3.14 (m, 1H), 3.03˜2.97 (m, 2H), 2.88(m, 1H), 2.69˜2.62 (m, 1H), 2.29 (m, 1H), 2.06˜1.97 (m, 2H), 1.93˜1.90(m, 2H), 1.20 (d, J=6.8 Hz, 3H).

2-(3S,4S)-[1-(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

16% yield. Chiral analytical HPLC (Column=chiralcel AD; Mobilephase=CO₂/MeOH/DEA 80/20/0.02 (v/v/v); Flow rate=2.5 mL/min):T_(R)=1.43. LC-MS: m/z 430.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (s,1H), 7.34˜7.30 (m, 1H), 6.91˜6.83 (m, 2H), 4.11˜4.05 (m, 2H), 3.75˜3.62(m, 2H), 3.62˜3.55 (m, 2H), 3.41˜3.33 (m, 2H), 3.01 (d, J=9.6 Hz, 1H),2.76˜2.74 (m, 1H), 2.59˜2.55 (m, 1H), 2.42˜2.40 (m, 1H), 2.12˜2.02 (m,2H), 1.95˜1.86 (m, 3H), 1.21 (d, J=6.8 Hz, 3H).

2-(3R,4R)-[1-(2,4-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

16% yield. Chiral analytical HPLC (Column=chiralcel AD; Mobilephase=CO₂/IPA/DEA 60/40/0.04 (v/v/v); Flow rate=2.4 mL/min): T_(R)=3.81.LC-MS: m/z 430.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.80 (s, 1H),7.36˜7.27 (m, 1H), 6.93˜6.84 (m, 2H), 4.11˜4.08 (m, 2H), 3.77˜3.76 (m,2H), 3.63˜3.56 (m, 2H), 3.43˜3.34 (m, 2H), 3.01 (d, J=10.2 Hz, 1H),2.77˜2.76 (m, 1H), 2.61˜2.58 (m, 1H), 2.44˜2.40 (m, 1H), 2.15˜2.03 (m,2H), 1.97˜1.87 (m, 3H), 1.22 (d, J=10.0 Hz, 3H).

2-(1-(4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(4-fluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

39% yield. LC-MS: m/z 422.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ8.41˜8.38 (m, 2H), 7.87 (s, 1H), 7.40˜7.32 (m, 4H), 7.15˜7.10 (m, 2H),3.62 (s, 2H), 2.98 (m, 1H), 2.88˜2.78 (m, 2H), 2.71˜2.67 (m, 1H),2.30˜2.26 (m, 1H), 2.01˜1.97 (m, 1H), 1.12 (d, J=6.8 Hz, 3H).

2-(4-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

36% yield. LC-MS: m/z 478 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.74 (s,1H), 7.32 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 4.00 (m, 2H), 3.73(d, J=12.8 Hz, 1H), 3.57˜3.48 (m, 3H), 3.35˜3.30 (m, 2H), 2.95 (d,J=10.0 Hz, 1H), 2.73˜2.71 (m, 1H), 2.40 (m, 1H), 2.38 (m, 1H), 1.89˜1.82(m, 5H), 1.15 (d, J=6.8 Hz, 3H).

2-(1-(2-chloro-4-methoxybenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

27% yield. LC-MS: m/z 458.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.77 (s,1H), 7.25 (d, J=8.4 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 6.82˜6.79 (dd,J=8.4, 2.8 Hz, 1H), 4.08˜4.05 (m, 2H), 3.79 (s, 3H), 3.79˜3.61 (m, 2H),3.61˜3.55 (m, 2H), 3.44˜3.00 (m, 2H), 3.02 (m, 1H), 2.76˜2.74 (m, 1H),2.62˜2.58 (m, 1H), 2.42˜2.37 (m, 1H), 2.15˜2.00 (m, 2H), 1.99˜1.86 (m,3H), 1.26 (d, J=12.4 Hz, 3H).

2-(4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. LC-MS: m/z 446 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d,J=8.4 Hz, 1H), 7.96 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.72 (s, 1H),4.02˜3.88 (m, 3H), 3.88˜3.86 (m, 1H), 3.53˜3.46 (m, 2H), 3.43˜3.29 (m,2H), 3.05 (m, 1H), 2.77 (m, 1H), 2.67 (m, 1H), 2.46 (m, 1H), 2.09˜1.91(m, 3H), 1.83˜1.78 (m, 2H), 1.19 (d, J=6.8 Hz, 3H).

2-[1-(5-Methoxy-2-methyl-penta-2,4-dienyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

20% yield. LC-MS: m/z 424.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (s,1H), 7.27 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.11˜4.05 (m, 2H),3.79 (s, 3H), 3.78 (m, 1H), 3.61˜3.55 (m, 2H), 3.50˜3.36 (m, 3H),2.97˜2.94 (d, J=10.0 Hz, 1H), 2.73 (m, 1H), 2.49˜2.41 (m, 2H), 2.13˜2.02(m, 3H), 1.92˜1.86 (m, 2H), 1.20 (d, J=6.8 Hz, 3H).

2-(4-methyl-1-(pyridin-4-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

12% yield. LC-MS: m/z 395.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.60 (d,J=5.2 Hz, 2H), 7.82 (s, 1H), 7.29 (d, J=5.2 Hz, 2H), 4.11 (m, 2H), 3.81(d, J=13.6 Hz, 1H), 3.65˜3.55 (m, 3H), 3.44˜3.38 (m, 2H), 3.03 (d,J=10.0 Hz, 1H), 2.81˜2.79 (m, 1H), 2.60˜2.55 (m, 1H), 2.48˜2.45 (m, 1H),2.16˜2.03 (m, 2H), 1.97˜1.74 (m, 3H), 1.24 (d, J=6.0 Hz, 3H)

2-(4-Methyl-1-pyridin-2-ylmethyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

7% yield. LC-MS: m/z 395.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.43(d, J=4.8 Hz, 1H), 7.75˜7.70 (m, 1H), 7.60 (s, 1H), 7.40 (d, J=8.0 Hz,1H), 7.24˜7.21 (m, 1H), 3.93 (m, 2H), 3.82˜3.71 (m, 2H), 3.52˜3.46 (m,2H), 3.10˜3.05 (m, 1H), 2.98˜2.94 (m, 1H), 2.87˜2.76 (m, 2H), 2.56˜2.53(m, 1H), 2.21˜2.17 (m, 1H), 1.93˜1.87 (m, 2H), 1.81˜1.78 (m, 2H), 1.07(d, J=7.2 Hz, 3H).

2-(4-methyl-1-(pyrimidin-5-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

44% yield. LC-MS: m/z 396.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.17 (br.s, 1H), 8.75 (s, 2H), 7.79 (s, 1H), 4.09˜4.05 (m, 2H), 3.73 (s, 2H),3.61˜3.54 (m, 2H), 3.47˜3.31 (m, 2H), 3.06 (d, J=6.0 Hz, 1H), 2.83˜2.80(m, 1H), 2.66˜2.61 (dd, J=10.0, 7.2 Hz, 1H), 2.47˜2.44 (m, 1H),2.12˜1.96 (m, 2H), 1.94˜1.74 (m, 3H), 1.25 (d, J=6.8 Hz, 3H).

2-[1-(4-Diethylamino-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

35% yield. LC-MS: m/z 465.3 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (s,1H), 7.17 (d, J=8.4 Hz, 2H), 6.65 (d, J=8.4 Hz, 2H), 4.11˜4.05 (m, 2H),3.76˜3.73 (d, J=12.4 Hz, 1H), 3.62˜3.55 (m, 2H), 3.49˜3.30 (m, 7H), 2.98(d, J=10.0 Hz, 1H), 2.70 (m, 1H), 2.46˜2.39 (m, 2H), 2.15˜1.81 (m, 5H),1.19 (d, J=7.2 Hz, 3H), 1.16˜1.13 (t, J=7.2 Hz, 6H).

2-(1-(furan-2-ylmethyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

35% yield. LC-MS: m/z 384.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.80 (s,1H), 7.41 (d, J=2.0 Hz, 1H), 6.34 (dd, J=2.0, 2.8 Hz, 1H), 6.26 (d,J=2.8 Hz, 1H), 4.11˜4.07 (m, 2H), 3.88˜3.84 (d, J=14.0 Hz, 1H),3.67˜3.56 (m, 3H), 3.45˜3.37 (m, 2H), 3.03 (d, J=10.0 Hz, 1H), 2.77˜2.74(m, 1H), 2.61˜2.58 (m, 1H), 2.45˜2.42 (m, 1H), 2.14˜1.98 (m, 3H),1.92˜1.88 (m, 2H), 1.21 (d, J=7.2 Hz, 3H)

2-(1-((1H-imidazol-2-yl)methyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

5% yield. LC-MS: m/z 384.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.44(br. s, 2H), 7.75 (s, 1H), 7.11 (s, 1H), 4.08˜4.06 (m, 2H), 3.87 (s,2H), 3.65˜3.53 (m, 3H), 3.18˜3.14 (dd, J=7.6, 8.8 Hz, 1H), 3.07˜3.00 (m,2H), 2.93˜2.88 (m, 1H), 2.73˜2.69 (m, 1H), 2.38˜2.34 (dd, J=7.6, 9.2 Hz,1H), 2.07˜1.91 (m, 4H), 1.09 (d, J=6.8 Hz, 3H).

2-((3S,4S)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

45% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH/DEA 80/20:0.3; Flow rate=1.0 mL/min): T_(R)=7.44.LC-MS: m/z=304.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.49 (s, 1H),3.96˜3.93 (m, 2H), 3.53˜3.31 (m, 6H), 2.82˜2.77 (m, 1H), 2.69˜2.66 (m,1H), 2.64˜2.53 (m, 1H), 1.95˜1.88 (m, 2H), 1.82˜1.78 (m, 2H), 1.10 (d,J=6.8 Hz, 3H).

2-((3R,4R)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

45% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH/DEA 80/20:0.3; Flow rate=1.0 mL/min): T_(R)=9.93.LC-MS: m/z 304.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.42 (br. s, 2H),7.63 (s, 1H), 3.97˜3.93 (m, 2H), 3.68˜3.41 (m, 6H), 3.05˜2.99 (m, 1H),2.96˜2.91 (m, 1H), 2.70˜2.66 (m, 1H), 1.95˜1.90 (m, 2H), 1.82˜1.78 (m,2H), 1.10 (d, J=6.8 Hz, 3H).

4((3-methyl-4-(4-oxo-7-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroimidazo[1,5-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl)methyl)benzonitrile

36% yield. LC-MS: m/z 419.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.63(d, J=7.6 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J=7.6 Hz, 2H), 3.96˜3.93 (m,2H), 3.76˜3.72 (d, J=13.6 Hz, 1H), 3.70˜3.66 (d, J=13.6 Hz, 1H),3.53˜3.40 (m, 3H), 3.05˜3.00 (dd, J=8.0, 8.8 Hz, 1H), 2.91˜2.84 (m, 2H),2.80˜2.75 (m, 1H), 2.60˜2.57 (m, 1H), 2.21˜2.17 (m, 1H), 1.95˜1.90 (m,2H), 1.81˜1.78 (m, 2H), 1.10 (d, J=6.8 Hz, 3H).

2-(1-(2-chloro-4-fluorobenzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

72% yield. LC-MS: m/z 446 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.77 (s,1H), 7.35˜7.31 (m, 1H), 7.19˜7.16 (m, 1H), 7.01˜6.99 (m, 1H), 4.10˜4.05(m, 2H), 3.83 (d, J=12.8 Hz, 1H), 3.72 (d, J=12.8 Hz, 1H), 3.61˜3.55 (m,2H), 3.40˜3.30 (m, 2H), 3.03 (d, J=10.0 Hz, 1H), 2.77 (m, 1H), 2.65˜2.61(m, 1H), 2.41˜2.39 (m, 1H), 2.10˜2.03 (m, 2H), 1.95˜1.88 (m, 3H), 1.22(d, J=8.8 Hz, 3H).

2-(1-(4-(dimethylamino)benzyl)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

25% yield. LC-MS: m/z 437 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (s,1H), 7.22 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.10˜4.05 (m, 2H),3.79 (d, J=12.8 Hz, 1H), 3.61˜3.55 (m, 2H), 3.45˜3.36 (m, 3H), 2.97 (d,J=8.0 Hz, 1H), 2.93 (s, 6H), 2.88 (m, 1H), 2.72 (m, 1H), 2.48˜2.40 (m,2H), 2.12˜2.01 (m, 2H), 1.91˜1.85 (m, 2H), 1.19 (d, J=6.8 Hz, 3H).

2-(4-methyl-1-(4-methylbenzyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

62% yield. LC-MS: m/z 408 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.05 (br.s, 1H), 7.79 (s, 1H), 7.24 (d, J=7.2 Hz, 2H), 7.17 (d, J=7.2 Hz, 2H),4.10˜4.05 (m, 2H), 3.82 (d, J=12.4 Hz, 1H), 3.61˜3.55 (m, 2H), 3.51 (d,J=12.8 Hz, 1H), 3.41˜3.37 (m, 2H), 2.99 (d, J=10.0 Hz, 1H), 2.74 (d,J=4.4 Hz, 1H), 2.52˜2.42 (m, 2H), 2.32 (s, 3H), 2.13˜2.01 (m, 2H),1.95˜1.85 (m, 3H), 1.20 (d, J=6.4 Hz, 3H).

2-(1-Cyclohexylmethyl-4-methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

37% yield. LC-MS: m/z 400.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.79 (s,1H), 4.09˜4.05 (m, 2H), 3.63˜3.59 (m, 2H), 3.43˜3.41 (m, 2H), 3.09˜3.06(d, J=11.6 Hz, 1H), 2.75 (m, 1H), 2.41˜2.44 (m, 1H), 2.37˜2.34 (m, 3H),2.17˜2.01 (m, 2H), 1.90-1.93 (m, 3H), 1.80˜1.76 (m, 5H), 1.68˜1.65 (m,1H), 1.46˜1.43 (m, 1H), 1.24 (m, 2H), 1.21 (d, J=7.2 Hz, 3H), 0.98 (m,2H).

2-(4-Methyl-1-pyridin-3-ylmethyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

60% yield. LC-MS: m/z 395.2 [M+1]⁺. ¹HNMR (400 MHz, CDCl₃): δ 8.55 (m,2H), 7.80 (s, 1H), 7.78 (m, 1H), 7.37˜7.35 (m, 1H), 4.08 (m, 2H),3.81˜3.78 (d, J=12.8 Hz, 1H), 3.67˜3.64 (d, J=12.8 Hz, 1H), 3.62˜3.58(m, 2H), 3.41˜3.38 (m, 2H), 2.99 (d, J=10.0 Hz, 1H), 2.79˜2.77 (m, 1H),2.59˜2.57 (m, 1H), 2.50˜2.40 (m, 1H), 1.99˜1.89 (m, 5H), 1.22 (d, J=7.2Hz, 3H).

2-[1-(2,6-Difluoro-benzyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

9% yield. LC-MS: m/z 430.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.78 (s,1H), 7.28 (m, 1H), 6.97˜6.94 (t, J=8.0 Hz, 2H), 4.10˜4.06 (m, 2H), 3.91(s, 2H), 3.61˜3.55 (m, 2H), 3.40˜3.38 (m, 2H), 3.15 (m, 1H), 2.74˜2.62(m, 2H), 2.42 (m, 1H), 2.10˜2.02 (m, 3H), 1.90˜1.87 (m, 2H), 1.19 (d,J=7.2 Hz, 3H).

2-[4-Methyl-1-(5-methyl-thiophen-2-ylmethyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z=414.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.81 (s,1H), 6.73 (d, J=3.3 Hz, 1H), 6.58˜6.57 (m, 1H), 4.13˜4.06 (m, 2H), 3.97(d, J=13.5 Hz, 1H), 3.67 (d, J=13.5 Hz, 1H), 3.64˜3.55 (m, 2H),3.48˜3.38 (m, 2H), 3.08 (d, J=9.9 Hz, 1H), 2.78˜2.75 (m, 1H), 2.53˜2.43(m, 5H), 2.16˜1.88 (m, 5H), 1.22 (d, J=7.2 Hz, 3H).

2-[1-(5-Chloro-thiophen-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

20% yield. LC-MS: m/z=434.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s,1H), 6.77˜6.75 (m, 2H), 4.11˜4.06 (m, 2H), 3.94 (d, J=14.4 Hz, 1H), 3.69(d, J=13.2 Hz, 1H), 3.62˜3.56 (m 2H), 3.47˜3.42 (m, 2H), 3.10 (d, J=10.0Hz, 1H), 2.79˜2.78 (m, 1H), 2.55˜2.43 (m, 2H), 2.15˜1.96 (m, 2H),1.92˜1.90 (m, 3H), 1.22 (d, J=6.8 Hz, 3H).

2-[4-Methyl-1-(4-pyrrolidin-1-yl-benzyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

10% yield. LC-MS: m/z=463.3 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.80 (s,1H), 7.19 (d, J=8.4 Hz, 2H), 6.54 (d, J=8.7 Hz, 2H), 4.11˜4.03 (m, 2H),3.78 (d, J=12.9 Hz, 1H), 3.62˜3.54 (m 2H), 3.44˜3.35 (m, 3H), 3.28˜3.23(m, 4H), 2.98˜2.95 (m, 1H), 2.72˜2.70 (m, 1H), 2.47˜2.42 (m, 2H),2.17˜1.85 (m, 9H), 1.19 (d, J=6.9 Hz, 3H).

2-[1-(4-Fluoro-benzyl)-4-methoxy-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

19% yield. LC-MS: m/z=428.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s,1H), 7.34˜7.31 (m, 2H), 7.08˜7.04 (m, 2H), 4.10˜4.07 (m, 2H), 3.99˜3.97(m, 1H), 3.84 (d, J=12.4 Hz, 1H), 3.61˜3.50 (m, 4H), 3.39 (s, 3H), 3.16(d, J=6.4 Hz, 1H), 3.99 (d, J=9.6 Hz, 1H), 2.72˜2.69 (m, 1H), 2.35˜2.30(m, 1H), 2.15˜2.01 (m, 2H), 1.90˜1.88 (m, 2H), 1.25˜1.24 (m, 1H).

2-[4-Methoxy-1-(4-methyl-benzyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

13% yield. LC-MS: m/z=424.3 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.80 (s,1H), 7.25 (d, J=6.6 Hz, 2H), 7.17 (d, J=7.8 Hz, 2H), 4.09˜4.00 (m, 3H),3.88 (d, J=12.6 Hz, 1H), 3.61˜3.53 (m, 4H), 3.44˜3.40 (m, 1H), 3.37 (s,3H), 3.19˜3.17 (m, 1H), 3.07˜3.03 (m, 1H), 2.77˜2.76 (m, 1H), 2.41˜2.37(m, 1H), 2.33 (s, 3H), 2.13˜1.99 (m, 2H), 1.90˜1.96 (m, 2H).

2-[4-Methoxy-1-(4-methoxy-benzyl)-pyrrolidin-3-yl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

25% yield. LC-MS: m/z=440.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s,1H), 7.27 (d, J=6.0 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.09˜4.07 (m, 2H),3.99˜3.96 (m, 1H), 3.79 (s, 3H), 3.61˜3.51 (m, 4H), 3.38 (s, 3H),3.15˜3.13 (m, 1H), 3.00˜2.97 (m, 1H), 2.69˜2.65 (m, 1H), 2.34˜2.30 (m,1H), 2.13˜2.00 (m, 3H), 1.90˜1.87 (m, 3H).

Example 22-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

To a solution of compound 6 (70 mg, 0.296 mmol) and potassium carbonate(70 mg, 0.296 mmol) in acetonitrile (10 mL) was added benzyl bromide (70mg, 0.296 mmol). The resulting solution was stirred at room temperaturefor 2 h. LC-MS showed that the reaction was complete. The reaction wasquenched with water (40 mL), and the reaction mixture was extracted withCH₂Cl₂ (30 mL×3). The combined organic phases were washed with brine (30mL), dried over Na₂SO₄ and concentrated in vacuum. The residue waspurified by preparative TLC (CH₂Cl₂/MeOH=10:1) to afford the desiredproduct (28.6 mg, 25% yield) as a white solid. LC-MS: m/z 394.2 [M+1]⁺.¹H NMR (400 MHz, CD₃OD-d4): δ 7.60 (s, 1H), 7.29˜7.22 (m, 4H), 7.19˜7.17(m, 1H), 3.95˜3.92 (m, 2H), 3.69˜3.58 (m, 2H), 3.52˜3.46 (m, 3H), 3.21(m, 1H), 3.06˜3.04 (m, 1H), 2.91˜2.76 (m, 2H), 2.58˜2.56 (m, 1H), 2.16(m, 1H), 1.89˜1.81 (m, 2H), 1.78 (m, 2H), 1.27 (d, J=6.8 Hz, 3H).

The racemic mixture of2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-onewas submitted for preparative chiral HPLC (Column=chiralpak OD-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=25 mL/min; UV: 230 nm; 30 mg/injin) and gave two enantiomers:

2-((3S,4S)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

80% yield. Chiral analytical HPLC (Column=chiralpak OD-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=5.85. LC-MS: m/z394.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.79 (s, 1H), 7.37˜7.35 (m,4H), 7.31˜7.29 (m, 1H), 4.11˜4.05 (m, 2H), 3.84˜3.81 (d, J=12.4 Hz, 1H),3.62˜3.55 (m, 3H), 3.43˜3.38 (m, 2H), 2.99˜2.96 (d, J=10.4 Hz, 1H),2.75˜2.73 (m, 1H), 2.53˜2.48 (m, 1H), 2.43˜2.41 (m, 1H), 2.13˜2.02 (m,2H), 1.95˜1.86 (m, 3H), 1.21 (d, J=7.2 Hz, 3H).

2-((3R,4R)-1-benzyl-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

80% yield. Chiral analytical HPLC (Column=chiralpak OD-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=7.57. LC-MS: m/z394.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.79 (s, 1H), 7.37˜7.35 (m,4H), 7.31˜7.26 (m, 1H), 4.11˜4.05 (m, 2H), 3.84˜3.81 (d, J=12.4 Hz, 1H),3.62˜3.55 (m, 3H), 3.43˜3.37 (m, 2H), 2.99˜2.96 (d, J=10.0 Hz, 1H),2.75˜2.73 (m, 1H), 2.53˜2.48 (m, 1H), 2.43˜2.41 (m, 1H), 2.13˜2.02 (m,2H), 1.95˜1.85 (m, 3H), 1.21 (d, J=7.2 Hz, 3H).

The following compounds were prepared in a similar way:

7-(4-Fluoro-phenyl)-2-(4-methyl-1-pyrimidin-2-ylmethyl-pyrrolidin-3-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

40% yield. LC-MS: m/z 405.9 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.76(d, J=4.8 Hz, 2H), 8.15 (m, 2H), 7.84 (s, 1H), 7.42 (t, J=4.8 Hz, 1H),7.20˜7.16 (d, J=8.8 Hz, 2H), 4.62˜4.47 (m, 3H), 4.01˜3.91 (m, 3H),3.30˜3.20 (m, 1H), 2.94˜2.86 (m, 1H), 1.24 (d, J=6.4 Hz, 3H).

7-(4-fluorophenyl)-2-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=7.68. LC-MS: m/z406.2 [M+1]⁺. ¹H NMR (400 MHz, MeOH-d4): δ 8.74 (d, J=5.2 Hz, 2H),8.28˜8.25 (m, 2H), 7.78 (s, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.04 (d,J=15.2 Hz, 1H), 4.87 (d, J=15.2 Hz, 1H), 3.19 (m, 2H), 2.89-2.82 (m,3H), 2.31 (m, 1H), 1.11 (d, J=6.8 Hz, 3H).

7-(4-fluorophenyl)-2-((3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

30% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=9.39. LC-MS: m/z406.2 [M+1]⁺. ¹H NMR (400 MHz, MeOH-d4): δ 8.74 (d, J=4.8 Hz, 2H),8.28˜8.25 (m, 2H), 7.78 (s, 1H), 7.32 (m, 1H), 7.18 (m, 2H), 4.04 (d,J=15.6 Hz, 1H), 4.87 (d, J=15.6 Hz, 1H), 3.19 (m, 2H), 2.89-2.82 (m,3H), 2.31 (m, 1H), 1.11 (d, J=6.8 Hz, 3H).

2-(4-Methyl-1-pyrimidin-2-ylmethyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

33% yield. LC-MS: m/z 396.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 8.73(d, J=5.2 Hz, 2H), 7.62 (s, 1H), 7.30 (t, J=4.8 Hz, 1H), 4.08˜4.04 (d,J=15.6 Hz, 1H), 3.96˜3.86 (m, 3H), 3.54˜3.44 (m, 3H), 3.26˜3.15 (m, 2H),2.85˜2.82 (m, 2H), 2.52 (m, 1H), 2.30˜2.28 (m, 1H), 1.92˜1.89 (m, 2H),1.88˜1.79 (m, 2H), 1.11 (d, J=7.2 Hz, 3H).

2-((3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

29% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=6.63. LC-MS: m/z396 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.84 (d, J=4.8 Hz, 2H), 7.81 (s,1H), 7.23 (t, J=4.8 Hz, 1H), 4.30 (d, J=16.8 Hz, 1H), 4.07 (m, 2H), 3.87(d, J=16.8 Hz, 1H), 3.64˜3.57 (m, 2H), 3.51˜3.44 (m, 2H), 3.26 (d,J=10.0 Hz, 1H), 2.83˜2.81 (m, 1H), 2.63˜2.60 (m, 1H), 2.51˜2.48 (m, 1H),2.30˜2.26 (m, 1H), 2.12˜2.05 (m, 2H), 1.95˜1.89 (m, 2H), 1.27 (d, J=7.2Hz, 3H).

2-((3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

29% yield. Chiral analytical HPLC (Column=chiralcel OJ-H; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=8.13. LC-MS: m/z396 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.84 (d, J=4.8 Hz, 2H), 7.81 (s,1H), 7.23 (t, J=4.8 Hz, 1H), 4.30 (d, J=16.8 Hz, 1H), 4.07 (m, 2H), 3.87(d, J=16.8 Hz, 1H), 3.64˜3.57 (m, 2H), 3.51˜3.44 (m, 2H), 3.26 (d,J=10.0 Hz, 1H), 2.83˜2.81 (m, 1H), 2.62˜2.58 (m, 1H), 2.49-2.47 (m, 1H),2.29˜2.25 (m, 1H), 2.12˜2.05 (m, 2H), 1.95˜1.89 (m, 2H), 1.27 (d, J=7.2Hz, 3H).

2-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

32% yield. LC-MS: m/z=410.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.86 (s,1H), 7.46˜7.43 (m, 5H), 4.77˜4.71 (m, 1H), 4.53˜4.35 (m, 2H), 4.23˜4.18(m, 1H), 4.07˜4.04 (m, 2H), 3.81˜3.71 (m, 3H), 3.56˜3.46 (m, 2H), 3.42(s, 3H), 3.38˜3.31 (m, 2H), 2.10˜2.01 (m, 2H), 1.88˜1.83 (m, 2H).

2-(3S,4S)-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

40% yield. Chiral analytical HPLC (Column=chiralcel AD-H; Mobilephase=n-Hexane/EtOH 60/40; Flow rate=0.6 mL/min): T_(R)=10.8. LC-MSm/z=410.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.40˜7.34 (m,5H), 4.10˜4.07 (m, 2H), 4.00˜3.97 (m, 1H), 3.88 (d, J=12.4 Hz, 1H),3.62˜3.53 (m, 4H), 3.44˜3.37 (m, 4H), 3.15 (d, J=6.4 Hz, 1H), 2.99 (d,J=10.0 Hz, 1H), 2.72˜2.68 (m, 1H), 2.36˜2.32 (m, 1H), 2.13˜2.03 (m, 2H),1.91˜1.87 (m, 2H).

2-(3R,4R)-(1-Benzyl-4-methoxy-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

40% yield. Chiral analytical HPLC (Column=chiralcel AD-H; Mobilephase=n-Hexane/EtOH 60/40; Flow rate=0.6 mL/min): T_(R)=11.9. LC-MS:m/z=410.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.39˜7.29 (m,5H), 4.10˜4.07 (m, 2H), 3.99˜3.96 (m, 1H), 3.88 (d, J=12.4 Hz, 1H),3.62˜3.52 (m, 4H), 3.41˜3.38 (m, 4H), 3.15 (d, J=6.0 Hz, 1H), 2.99 (d,J=10.0 Hz, 1H), 2.72˜2.68 (m, 1H), 2.36˜2.32 (m, 1H), 2.13˜2.03 (m, 2H),1.91˜1.87 (m, 2H).

2-(4-Methyl-1-pyrimidin-4-ylmethyl-pyrrolidin-3-yl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

5% yield. LC-MS: m/z=396.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 9.15(s, 1H), 8.74 (d, J=5.2 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J=6.0 Hz, 1H),4.07˜4.04 (m, 2H), 3.98 (d, J=15.2 Hz, 1H), 3.87 (d, J=15.2 Hz, 1H),3.64˜3.55 (m, 3H), 3.24˜3.20 (m, 1H), 3.13˜3.12 (m, 1H), 3.01˜2.97 (m,1H), 2.93˜2.88 (m, 1H), 2.70˜2.66 (m, 1H), 2.38˜2.34 (m, 1H), 2.06˜1.99(m, 2H), 1.92˜1.89 (m, 2H), 1.21 (d, J=6.8 Hz, 3H).

Example 32-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-pyridin-3-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

The procedure for the preparation of this compound was similar to thatof compound 7.

60% yield. LC-MS: m/z 387.1 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 9.37(br. s, 1H), 8.60 (d, J=8.0 Hz, 1H), 8.51 (m, 1H), 7.97 (br. s, 1H),7.89 (m, 1H), 7.81 (s, 1H), 7.50˜7.47 (m, 1H), 7.30˜7.14 (m, 4H),3.74˜3.65 (m, 2H), 3.12˜3.09 (m, 1H), 3.01˜2.92 (m, 2H), 2.85˜2.81 (m,1H), 2.63˜2.60 (m, 1H), 2.26˜2.23 (m, 1H), 1.11 (d, J=6.4 Hz, 3H).

2-(1-benzyl-4-methylpyrrolidin-3-yl)-7-(4-(trifluoromethoxy)phenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

47% yield. LC-MS: m/z 470.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 8.49(d, J=9.2 Hz, 2H), 7.90 (s, 1H), 7.54˜7.52 (d, J=8.0 Hz, 2H), 7.34˜7.28(m, 3H), 7.25˜7.23 (m, 1H), 3.64 (s, 2H), 2.99˜2.87 (m, 3H), 2.85˜2.82(m, 1H), 2.28 (m, 1H), 2.00 (m, 1H), 1.13 (d, J=6.8 Hz, 3H).

2-(1-Benzyl-4-methyl-pyrrolidin-3-yl)-7-pyridin-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

20% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.72 (d, J=7.2 Hz, 2H), 8.29 (d,J=3.6 Hz, 2H), 8.01 (s, 1H), 7.39˜7.31 (m, 5H), 3.87 (m, 1H), 3.65 (m,1H), 3.49˜3.43 (m, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.53 (m, 1H), 2.24(m, 2H), 1.27 (d, J=7.2 Hz, 3H).

2-(1-benzyl-4-methylpyrrolidin-3-yl)-7-(2,4-difluorophenyl)imidazo[1,5-f][1,2,4]triazin-4(3H)-one

31% yield. LC-MS: m/z 422 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.99 (s,1H), 7.78˜7.72 (m, 1H), 7.40˜7.28 (m, 5H), 7.03˜6.93 (m, 2H), 3.82 (d,J=12.4 Hz, 1H), 3.57 (d, J=12.4 Hz, 1H), 3.39 (t, J=8.4 Hz, 1H), 2.99(d, J=10.0 Hz, 1H), 2.72˜2.70 (m, 1H), 2.52˜2.40 (m, 2H), 1.92 (dd,J=8.0, 9.2 Hz, 1H), 1.17 (d, J=6.8 Hz, 3H).

Part II (Azetidine Series) Preparation of Intermediates2-Chloromethyl-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-oneScheme 6

3-(2-Benzyloxy-acetylamino)-3H-imidazole-4-carboxylic acid methyl ester(2)

To a solution of compound 1 (5.0 g, 35.4 mmol), benzyloxy-acetic acid(6.5 g, 39.0 mmol) and DIEA (19 ml, 106.3 mmol) in DMF (50 mL) on anice-water bath was added HATU (20.2 g, 53.1 mmol). The mixture wasstirred at ambient temperature overnight. After removal of the solvent,the residue was purified by chromatography on silica gel column (elutedwith PE/EtOAc=10:1 to 2:1) to afford compound 2 (8.7 g, 85% yield) as anoil. LC-MS: m/z 290.2 [M+H]⁺.

3-(2-Benzyloxy-acetylamino)-3H-imidazole-4-carboxylic acid amide (3)

Compound 2 (8.7 g, 30.1 mmol) and ammonium hydroxide (15 ml) werecombined in a sealed tube and heated to 70° C. under microwaveirradiation for 2 hours. The mixture was concentrated in vacuo to affordcompound 3 (7.3 g, 88% yield) as a white solid. LC-MS: m/z 275.1 [M+H]⁺.

2-Benzyloxymethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (4)

A solution of KOH (4.4 g, 78.5 mmol) in water (50 mL) was added dropwiseto a solution of compound 3 (7.3 g, 26.6 mmol) in EtOH (60 mL) at roomtemperature. The resulting solution was heated to 110° C. for 3 hours.After removal of the organic solvent, the mixture was poured into icewater and the pH was adjusted to 7.0 with 1M aqueous HCl solution. Thesuspension was filtered and the filtrate was dried to afford compound 4(4.9 g, 71% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 12.05(s, 1H), 8.45 (s, 1H), 7.74 (s, 1H), 7.39˜7.29 (m, 5H), 4.59 (s, 2H),4.36 (s, 2H). LC-MS: m/z 257.2 [M+H]⁺.

2-Benzyloxymethyl-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (5)

To a solution of compound 4 (4.9 g, 19.1 mmol) in THF (120 mL) was addedn-BuLi (23 mL) dropwise at −78° C. and the resulting reaction mixturewas stirred below −70° C. for one hour, followed by dropwise addition ofiodine (19.4 g, 76.3 mmol) in THF (60 mL) at the same temperature. Thereaction was allowed to warm to room temperature slowly. The reactionwas quenched with saturated aqueous Na₂SO₃ solution (60 mL), and it wasthen extracted with EtOAc (60 mL×3). The organic phases were combinedand dried over Na₂SO₄. The solid was filtered and the filtrate wasconcentrated in vacuo to give the crude product, which was purified bychromatography on silica gel column (eluted with PE/EtOAc=10:1 to 2:1)to afford compound 5 (4.1 g, 56% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6): δ 12.16 (s, 1H), 7.84 (s, 1H), 7.42˜7.29 (m, 5H), 4.62(s, 2H), 4.40 (s, 2H). LC-MS: m/z 383.2 [M+H]⁺.

2-Benzyloxymethyl-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(6)

To a solution of compound 5 (1.0 g, 2.61 mmol) in dioxane (12 mL) atroom temperature was added dropwise a solution of Cs₂CO₃ (2.5 g, 7.66mmol) in water (3 mL), followed by addition of Pd(PPh₃)₄ (300 mg, 0.26mmol) and4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(636 mg, 3.0 mmol). The reaction mixture was degassed by purging with N₂for 15 min. Then the mixture was heated to 125° C. under microwaveirradiation for 40 min. After removal the solvent, the residue waspurified by chromatography on silica gel column eluted withPE/EtOAc=10:1 to 1:5) to afford compound 6 (680 mg, 76% yield) as awhite solid. LC-MS: m/z 339.1 [M+H]⁺.

2-Hydroxymethyl-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(7)

To a solution of compound 6 (650 mg, 1.14 mmol) in MeOH (30 mL) wasadded Pd(OH)₂/C (120 mg). The reaction mixture was stirred under 50 psiof hydrogen at 70° C. until LC-MS showed that the starting material wasalmost consumed. The suspension was filtered through celite and washedwith MeOH (20 mL×2) and the filtrate was concentrated in vacuo to affordcompound 7 (410 mg, 85% yield) as a white solid. LC-MS: m/z 251.3[M+H]⁺.

2-Chloromethyl-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(8)

To a solution of compound 7 (400 mg, 1.6 mmol) in CH₂Cl₂ (50 mL) inice-water bath was added SOCl₂ (10 mL) dropwise. The resulting mixturewas then stirred at ambient temperature overnight. The reaction mixturewas concentrated in vacuo to afford compound 8 (370 mg, 86% yield) as awhite solid. LC-MS: m/z 269.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 12.50(s, 1H), 8.02 (s, 1H), 4.57 (s, 2H), 3.95 (m, 2H), 3.48 (m, 3H), 1.88(m, 4H).

2-Acetyl-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

3-(2-Benzyloxy-propionylamino)-3H-imidazole-4-carboxylic acid methylester (9)

To a solution of compound 2 (4.2 g, 29.7 mmol), 2-Benzyloxy-propionicacid (5.5 g, 29.7 mmol) and DIEA (10 mL) in a mixture of DMF (1 mL) andTHF (50 mL) in ice-water bath was added HATU (13.5 g, 35.7 mmol). Theresulting mixture was then stirred at ambient temperature overnight.Water (100 mL) was added. The mixture was extracted with ethyl acetate(300 mL×2). The combined organic phases were concentrated to give acrude residue, which was purified by chromatography on silica gel column(eluted with PE/EtOAc=1:1 to 1:3) to afford compound 9 (8.2 g, 91%yield) as brown oil. LC-MS: m/z 304 [M+H]⁺.

3-(2-Benzyloxy-propionylamino)-3H-imidazole-4-carboxylic acid amide (10)

Compound 9 (8.2 g, 27 mmol) and ammonium hydroxide (100 mL) were mixedand heated to 60° C. for two hours. The reaction mixture wasconcentrated in vacuo to give compound 10 (7.8 g, 100% yield) as whitesolid. LC-MS: m/z 289 [M+H]⁺.

2-(1-Benzyloxy-ethyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one (11)

To a solution of compound 10 (1.5 g, 5.2 mmol) in EtOH (10 mL) was addeda solution of KOH (870 mg, 15.6 mmol) in H₂O (4 mL). Then the resultingmixture was heated at 100° C. under microwave heating for one hour.After removal of the solvent, the mixture was poured into ice water andpH was adjusted to 7 with 1M aqueous HCl solution. The suspension wasfiltered and the solid was dried to give compound 11 (1.06 g, 75% yield)as a white solid. LC-MS: m/z 271 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.70(br. s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.39˜7.32 (m, 5H), 4.60 (m,2H), 4.46 (q, J=6.4 Hz, 1H), 1.57 (d, J=6.4 Hz, 3H).

2-(1-Benzyloxy-ethyl)-7-iodo-3H-imidazo[5,1-f][1,2,4]triazin-4-one (12)

To a solution of compound 11 (1.2 g, 4.4 mmol) in THF (100 mL) was addedn-BuLi (2.5 M, 3.5 ml) dropwise at −78° C. over 30 minutes and theresulting reaction mixture was stirred below −70° C. for another onehour. Then a solution of iodine (2.2 g, 8.8 mmol) in THF (20 mL) wasadded dropwise and the dark brown mixture was allowed to warm up to roomtemperature slowly over one hour. The reaction was quenched withsaturated aqueous solution of Na₂SO₃ (60 mL), and then the mixture wasextracted with EtOAc (200 mL×2). The organic layers were combined anddried over Na₂SO₄, filtered and concentrated in vacuo to give the crudeproduct, which was purified by chromatography on silica gel column(eluted with PE/EtOAc=10:1 to 2:1) to afford compound 12 (450 mg, 25%yield) as a yellow solid. LC-MS: m/z 397 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.82 (br. s, 1H), 7.94 (s, 1H), 7.36˜7.32 (m, 5H), 4.65˜4.55(m, 3H), 1.60 (d, J=6.4 Hz, 3H).

2-(1-Benzyloxy-ethyl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(13)

To a solution of compound 12 (300 mg, 0.75 mmol) in dioxane (2 mL) wasadded a solution of Cs₂CO₃ (492 mg, 1.51 mmol) in H₂O (0.5 mL) dropwise,followed by addition of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(318 mg, 1.5 mmol) and Pd(PPh₃)₄ (86 mg, 0.075 mmol). The reactionmixture was degassed by purging with N₂ for 15 min. Then the reactionwas heated to 125° C. under microwave heating for 40 min. After removalof the solvent, the residue was purified by chromatography on silica gelcolumn (eluted with PE/EtOAc=10:1 to 1:5) to afford compound 13 (200 mg,75% yield) as white solid. LC-MS: m/z 353 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.82 (br. s, 1H), 7.91 (s, 1H), 7.37˜7.32 (m, 5H), 7.19 (br.s, 1H), 4.61 (m, 2H), 4.49 (q, J=6.8 Hz, 1H), 4.40 (m, 2H), 3.95 (t,J=5.2 Hz, 2H), 2.78 (m, 2H), 1.58 (d, J=6.4 Hz, 3H).

2-(1-Hydroxy-ethyl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(14)

To a solution of compound 13 (900 mg, 2.55 mmol) in MeOH (30 mL) wasadded Pd(OH)₂/C (120 mg). The mixture was stirred at 75° C. under H₂ (50psi) overnight. The suspension was filtered through Celite, washed withMeOH (20 mL×2). The combined organic phases were concentrated in vacuoto afford compound 14 (540 mg, 80% yield) as a white solid. LC-MS: m/z265 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 9.07 (br. s, 1H), 7.85 (s, 1H),4.84 (q, J=6.4 Hz, 1H), 4.11 (m, 2H), 3.59 (m, 2H), 3.44˜3.39 (m, 1H),2.14˜2.06 (m, 3H), 1.92˜1.88 (m, 2H), 1.64 (d, J=6.4 Hz, 3H).

2-Acetyl-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one(15)

To a solution of compound 14 (400 mg, 1.6 mmol) in CH₂Cl₂ (50 mL) wasadded MnO₂ (520 mg, 6 mmol). The mixture was heated at 50° C. overnight.The reaction mixture was filtered and washed with ethyl acetate. Thefiltrate was concentrated in vacuo to afford compound 15 (370 mg, 86%yield) as a white solid. LC-MS: m/z 263 [M+H]⁺. ¹H NMR (300 MHz, CDCl₃):δ 8.99 (br. s, 1H), 7.93 (s, 1H), 4.16˜4.12 (m, 2H), 3.67˜3.59 (m, 2H),3.54˜3.48 (m, 1H), 2.72 (s, 3H), 2.19˜2.11 (m, 2H), 2.00˜1.96 (m, 2H).

Preparation of Target Compounds: Example 42-[3-(4-Fluoro-phenoxy)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

To a solution of compound 15 (40 mg, 0.15 mmol) and compound A1 (50 mg,0.30 mmol) in CH₃CN (40 mL) was added DiEA (0.5 mL, 3.0 mmol). Theresulting solution was heated to 70° C. for 2 h. The reaction was foundto be complete by monitoring with TLC. The reaction was concentrated invacuum. The residue was purified by column chromatography on silica gel(eluted with EtOAc/MeOH 100:1 to 30:1) to afford the desired product (25mg, 42% yield) as a white solid. LC-MS: m/z 400.1 [M+1]⁺. ¹H NMR (400MHz, CD₃OD-d4): δ 8.44 (br. s, 1H), 7.65 (s, 1H), 6.93 (m, 2H), 6.73 (m,2H), 3.98˜3.95 (m, 2H), 3.90˜3.86 (m, 2H), 3.59 (s, 2H), 3.54˜3.46 (m,3H), 3.32 (m, 2H), 1.95˜1.81 (m, 5H).

The following compounds were prepared in a similar way:

2-[3-(4-Methoxy-phenyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

31% yield. LC-MS: m/z 396.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.23˜7.21 (d, J=8.4 Hz, 2H), 6.90˜6.88 (d, J=8.4 Hz, 2H), 4.11˜4.08(m, 2H), 3.88˜3.86 (m, 2H), 3.84 (s, 3H), 3.81˜3.72 (m, 1H), 3.62 (s,2H), 3.59˜3.56 (m, 2H), 3.45˜3.41 (m, 1H), 3.38˜3.35 (m, 2H), 2.11˜2.04(m, 2H), 1.89˜1.82 (m, 2H).

7-(4-Fluoro-phenyl)-2-[3-(4-methoxy-phenyl)-azetidin-1-ylmethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

20% yield. LC-MS: m/z 406.1 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ8.38˜8.34 (m, 2H), 7.91 (s, 1H), 7.32˜7.29 (m, 4H), 6.92˜6.90 (d, J=8.8Hz, 2H), 3.97˜3.94 (m, 2H), 3.82 (s, 3H), 3.80˜3.77 (m, 1H), 3.75 (s,2H), 3.51˜3.47 (m, 2H).

7-(4-Fluoro-phenyl)-2-[3-(4-fluoro-phenyl)-azetidin-1-ylmethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

14% yield. LC-MS: m/z 394.1 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ8.19˜8.16 (m, 2H), 7.94 (s, 1H), 7.46˜7.42 (m, 2H), 7.33˜7.29 (m, 2H),7.17˜7.13 (m, 2H), 4.73˜4.65 (m, 2H), 4.61 (s, 2H), 4.50˜4.45 (m, 2H),4.36˜4.29 (m, 1H).

2-[3-(4-Fluoro-phenyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

18 mg, 20% yield. LC-MS: m/z 384.1[M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ7.62 (s, 1H), 7.30˜7.26 (m, 2H), 6.97˜6.93 (m, 2H), 3.96˜3.93 (m, 2H),3.83˜3.79 (m, 2H), 3.71˜3.67 (m, 1H), 3.55 (s, 2H), 3.53˜3.45 (m, 2H),3.38 (m, 1H), 3.33˜3.30 (m, 2H), 1.93˜1.87 (m, 2H), 1.82˜1.78 (m, 2H).

2-[3-(2,6-Difluoro-phenoxy)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

36% yield. LC-MS: m/z 418.1 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 12.20(br. s, 1H), 7.70 (s, 1H), 7.23˜7.19 (m, 3H), 5.08 (m, 1H), 4.70 (m,2H), 4.56 (s, 2H), 4.52˜4.48 (m, 2H), 3.97 (d, J=10.7 Hz, 2H), 3.52˜3.40(m, 3H), 1.85 (m, 4H).

7-(Tetrahydro-pyran-4-yl)-2-[3-(4-trifluoromethoxy-phenoxy)-azetidin-1-ylmethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

35% yield. LC-MS: m/z 466.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.16˜7.14 (d, J=8.8 Hz, 2H), 6.77˜6.74 (d, J=8.8 Hz, 2H), 4.84˜4.81(m, 1H), 4.11˜4.07 (m, 2H), 3.97˜3.93 (m, 2H), 3.67 (s, 2H), 3.61˜3.55(m, 2H), 3.44˜3.38 (m, 3H), 2.11˜2.04 (m, 2H), 1.91˜1.87 (m, 2H).

2-[3-(4-Dimethylamino-phenyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

26% yield. LC-MS: m/z 409.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.19˜7.17 (d, J=8.8 Hz, 2H), 6.74˜6.72 (d, J=8.8 Hz, 2H), 4.11˜4.08(m, 2H), 3.86˜3.82 (m, 2H), 3.72˜3.68 (m, 1H), 3.62˜3.56 (m, 4H),3.42˜3.37 (m, 1H), 3.35˜3.33 (m, 2H), 2.94 (s, 6H), 2.11˜2.05 (m, 2H),1.92˜1.89 (m, 2H).

2-(3-Phenoxy-azetidin-1-ylmethyl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

32% yield. LC-MS: m/z 382.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6): δ 11.73(br. s, 1H), 7.67 (s, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.82 (m, 2H),4.83 (m, 1H), 3.93˜3.84 (m, 4H), 3.54 (s, 2H), 3.47 (m, 2H), 3.32 (m,1H), 3.24 (m, 2H), 1.85 (m, 4H).

2-(3-Pyrimidin-2-yl-azetidin-1-ylmethyl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

12% yield. LC-MS: m/z=368.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d6): δ8.76˜8.75 (m, 2H), 7.65˜7.63 (m, 1H), 7.37˜7.35 (m, 1H), 3.98˜3.80 (m,5H), 3.58˜3.38 (m, 7H), 1.87˜1.81 (m, 4H).

2-[3-(4-Methyl-benzyloxy)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

9% yield. LC-MS: m/z=410.2 [M+1]⁺. ¹H NMR (300 MHz, CD₃OD-d4): δ 7.93(s, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.20 (d, J=8.1 Hz, 2H), 4.57˜4.60 (m,7H), 4.23˜4.26 (m, 2H), 4.05˜4.10 (m, 2H), 3.58˜3.66 (m, 3H), 2.34 (s,3H), 1.92˜2.00 (m, 4H).

2-(3-Benzyl-azetidin-1-ylmethyl)-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

23% yield. LC-MS: m/z=380.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.82 (s,1H), 7.31˜7.27 (m, 2H), 7.23˜7.21 (m, 1H), 7.14˜7.12 (m, 2H), 4.10˜4.07(m, 2H), 3.61˜3.50 (m, 6H), 3.43˜3.37 (m, 1H), 3.12˜3.09 (m, 2H),2.91˜2.89 (m, 2H), 2.84˜2.83 (m, 1H), 2.11˜2.083 (m, 2H), 1.91˜1.87 (m,2H).

2-[3-(4-Methoxy-phenoxymethyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z=426.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.84(s, 1H), 7.04 (d, J=12.0 Hz, 2H), 6.92 (d, J=12.0 Hz, 2H), 4.62 (m, 4H),4.46 (m, 2H), 4.13˜4.15 (m, 2H), 4.02˜4.07 (m, 2H), 3.78 (s, 3H),3.54˜3.60 (m, 3H), 3.37 (m, 1H), 1.89˜2.06 (m, 4H).

2-[3-(4-Pyrrolidin-1-yl-phenyl)-azetidin-1-ylmethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

23% yield. LC-MS: m/z=435.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.16 (d, J=8.8 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 4.11˜4.08 (m, 2H),3.86˜3.84 (m, 2H), 3.71˜3.67 (m, 1H), 3.62˜3.56 (m, 4H), 3.45˜3.39 (m,1H), 3.36˜3.33 (m, 2H), 3.29˜3.26 (m, 4H), 2.17˜2.10 (m, 2H), 2.08˜1.99(m, 4H), 1.92˜1.89 (m, 2H).

Example 52-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

To a solution of compound 15 (57 mg, 0.21 mmol) and compound A2 (43 mg,0.21 mmol) in THF (50 mL) was added Ti(Oi-Pr)₃ (1 mL). The mixture wasthen stirred at ambient temperature overnight. Then NaBH(OAc)₃ (200 mg,0.95 mmol) was added and the reaction was stirred at room temperatureovernight. The reaction mixture was poured into 10 ml of water and thepH of the solution was adjusted to 7 with a saturated aqueous solutionof NaHCO₃. The reaction mixture was extracted with ethyl acetate (100mL×2). The combined organic layers were dried over Na₂SO₄, and the solidwas filtered off. The filtrate was concentrated in vacuo to give a cruderesidue which was subjected to Prep-HPLC to afford the desired compound(7 mg, 7.8% yield) as a white solid. LC-MS: m/z 410.2 [M+H]⁺. ¹H NMR(400 MHz, CD₃OD-d4): δ 7.63 (s, 1H), 7.18 (dd, J=2.0, 7.2 Hz, 2H), 6.80(dd, J=2.0, 7.2 Hz, 2H), 3.98˜3.95 (m, 2H), 3.83˜3.73 (m, 2H), 3.68 (s,3H), 3.67˜3.63 (m, 1H), 3.56˜3.47 (m, 1H), 3.32˜3.22 (m, 2H), 1.96˜1.80(m, 4H), 1.31 (d, J=6.4 Hz, 3H).

The racemic mixture of2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-onewas submitted for preparative chiral HPLC (Column=chiralpak IA; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=12 mL/min; UV: 230 nm; 30 mg/injin) and gave two enantiomers:

2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

40% yield. Chiral analytical HPLC (Column=chiralpak IA; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=9.98. LC-MS(ESI) m/z=410.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s, 1H), 7.21(d, J=8.4 Hz, 2H), 6.88 (dd, J=1.6 Hz, J=6.4 Hz, 2H), 4.12˜4.08 (m, 2H),3.81 (s, 3H), 3.77˜3.68 (m, 3H), 3.63˜3.57 (m, 2H), 3.46˜3.40 (m, 2H),3.31˜3.28 (m, 1H), 3.23˜3.20 (m, 1H), 2.11˜2.07 (m, 2H), 1.93˜1.89 (m,2H), 1.33 (d, J=6.4 Hz, 3H).

2-{1-[3-(4-Methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

40% yield. Chiral analytical HPLC (Column=chiralpak IA; Mobilephase=n-Hexane/EtOH 70/30; Flow rate=1.0 mL/min): T_(R)=14.7. LC-MS(ESI) m/z=410.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s, 1H), 7.21(d, J=8.4 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.12-4.08 (m, 2H), 3.80 (s,3H), 3.77-3.74 (m, 1H), 3.72-3.68 (m, 2H), 3.62-3.57 (m, 2H), 3.46-3.40(m, 2H), 3.31-3.28 (m, 1H), 3.23-3.20 (m, 1H), 2.11-2.07 (m, 2H),1.93-1.90 (m, 2H), 1.32 (d, J=6.8 Hz, 3H).

The following compound was prepared in a similar way:

2-{1-[3-(4-Fluoro-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z 398.2 [M+H]⁺. ¹H NMR (400 MHz, MeOD-d4): δ 7.85(s, 1H), 7.26˜7.23 (m, 2H), 7.05˜7.01 (m, 2H), 4.12˜4.09 (m, 2H),3.80˜3.72 (m, 3H), 3.63˜3.57 (m, 2H), 3.47˜3.40 (m, 2H), 3.33˜3.29 (m,1H), 3.25˜3.22 (m, 1H), 2.12˜2.06 (m, 2H), 1.93˜1.90 (m, 2H), 1.31 (d,J=7.2 Hz, 3H).

2-{1-[3-(4-Fluoro-phenoxy)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

10% yield. LC-MS: (ESI) m/z=414.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ7.83 (s, 1H), 6.99˜6.94 (m, 2H), 6.71˜6.69 (m, 2H), 4.77˜4.74 (m, 1H),4.10˜4.08 (m, 2H), 3.86˜3.77 (m, 2H), 3.61˜3.56 (m, 2H), 3.49˜3.46 (m,1H), 3.42˜3.33 (m, 2H), 3.25˜3.21 (m, 1H), 2.11˜2.04 (m, 2H), 1.92˜1.88(m, 2H), 1.34 (d, J=6.4 Hz, 3H).

7-(Tetrahydro-pyran-4-yl)-2-[1-(3-p-tolyloxy-azetidin-1-yl)-ethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one

35% yield. LC-MS: m/z=410 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.84 (s,1H), 7.07 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 4.80˜4.76 (m, 1H),4.12˜4.07 (m, 2H), 3.87˜3.77 (m, 2H), 3.63˜3.55 (m, 2H), 3.49˜3.32 (m,3H), 3.24˜3.20 (m, 1H), 2.28 (s, 3H), 2.11˜2.06 (m, 2H), 1.93˜1.88 (m,2H), 1.33 (d, J=6.9 Hz, 3H).

2-[1-(3-Phenyl-azetidin-1-yl)-ethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

62% yield. LC-MS: m/z=380.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.37˜7.33 (m, 2H), 7.29˜7.24 (m, 3H), 4.11˜4.09 (m, 2H), 3.80˜3.73(m, 3H), 3.63˜3.57 (m, 2H), 3.47˜3.40 (m, 2H), 3.37˜3.34 (m, 1H),3.30˜3.25 (m, 1H), 2.16˜2.05 (m, 2H), 1.93˜1.90 (m, 2H), 1.33 (d, J=6.8Hz, 3H).

2-{1-[3-(3-Fluoro-4-methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

25% yield. LC-MS: m/z=428.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.04˜6.90 (m, 3H), 4.11˜4.09 (m, 2H), 3.89 (s, 3H), 3.76˜3.57 (m,5H), 3.46˜3.40 (m, 2H), 3.29˜3.26 (m, 1H), 3.22˜3.19 (m, 1H), 2.11˜2.04(m, 2H), 1.93˜1.90 (m, 2H), 1.33 (d, J=6.8 Hz, 3H).

2-{1-[3-(2-Fluoro-4-methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

36% yield. LC-MS: m/z=428.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.16 (dd, J=8.8 Hz, J=8.8 Hz, 1H), 6.68 (dd, J=2.4 Hz, J=6.8 Hz,1H), 6.59 (dd, J=2.4 Hz, J=12.0 Hz, 1H), 4.11˜4.08 (m, 2H), 3.88˜3.81(m, 2H), 3.79 (s, 3H), 3.75˜3.72 (m, 1H), 3.62˜3.57 (m, 2H), 3.46˜3.39(m, 2H), 3.36˜3.33 (m, 1H), 3.27˜3.23 (m, 1H), 2.14˜2.04 (m, 2H),1.93˜1.90 (m, 2H), 1.32 (d, J=6.4 Hz, 3H).

2-{1-[3-(4-Ethoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

18% yield. LC-MS: m/z=424.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.19 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.4 Hz, 2H), 4.11˜4.09 (m, 2H),4.05˜4.00 (m, 2H), 3.78˜3.66 (m, 3H), 3.63˜3.57 (m, 2H), 3.46˜3.40 (m,2H), 3.32˜3.29 (m, 1H), 3.24˜3.20 (m, 1H), 2.11˜2.05 (m, 2H), 1.93˜1.90(m, 2H), 1.41 (t, J=6.8 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H).

2-{1-[3-(4-Hydroxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

10% yield. LC-MS (ESI): m/z=396.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ7.91 (s, 1H), 7.27 (d, J=11.2 Hz, 2H), 6.84 (d, J=11.2 Hz, 2H),4.72˜4.65 (m, 3H), 4.44˜4.41 (m, 2H), 4.22˜4.19 (m, 1H), 4.11˜4.06 (m,2H), 3.69˜3.60 (m, 3H), 2.05˜1.92 (m, 4H), 1.70 (d, J=8.8 Hz, 3H).

2-{1-[3-(4-Pyrrolidin-1-yl-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-4a,7-dihydro-3H-imidazo[5,1-f][1,2,4]triazin-4-one

28% yield. LC-MS: m/z=449.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.15 (d, J=8.4 Hz, 2H), 6.54 (d, J=8.4 Hz, 2H), 4.11˜4.08 (m, 2H),3.74˜3.57 (m, 5H), 3.46˜3.40 (m, 2H), 3.27˜3.25 (m, 5H), 3.20˜3.17 (m,1H), 2.11˜2.08 (m, 2H), 2.05˜2.00 (m, 4H), 1.93˜1.90 (m, 2H), 1.32 (d,J=6.8 Hz, 3H).

2-{1-[3-(4-Dimethylamino-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

23% yield. LC-MS: m/z=423.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.83 (s,1H), 7.16 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 4.11˜4.08 (m, 2H),3.74˜3.69 (m, 1H), 3.68˜3.57 (m, 4H), 3.45˜3.40 (m, 2H), 3.30˜3.27 (m,1H), 3.21˜3.17 (m, 1H), 2.94 (s, 6H), 2.11˜2.08 (m, 2H), 1.93˜1.90 (m,2H), 1.32 (d, J=6.8 Hz, 3H).

7-(Tetrahydro-pyran-4-yl)-2-{1-[3-(4-trifluoromethoxy-phenyl)-azetidin-1-yl]-ethyl}-3H-imidazo[5,1-f][1,2,4]triazin-4-one

36% yield. LC-MS: m/z=464.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 8.92 (br.s, 1H), 7.84 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H),4.11˜4.08 (m, 2H), 3.81˜3.72 (m, 3H), 3.62˜3.57 (m, 2H), 3.47˜3.40 (m,2H), 3.34˜3.31 (m, 1H), 3.29˜3.26 (m, 1H), 2.14˜2.04 (m, 2H), 1.93˜1.89(m, 2H), 1.29 (d, J=8.8 Hz, 3H).

2-{1-[3-(4-Methoxy-benzyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

18% yield. LC-MS: m/z=424.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD-d4): δ 7.59(s, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 3.97˜3.94 (m,2H), 3.65 (s, 3H), 3.54˜3.43 (m, 6H), 3.10˜3.07 (m, 2H), 2.72 (m, 3H),1.94˜1.88 (m, 2H), 1.85˜1.77 (m, 2H), 1.25 (d, J=6.8 Hz, 3H).

2-{1-[3-(3-Chloro-4-methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

26% yield. LC-MS: m/z=444.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.29 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H),4.12-4.09 (m, 2H), 3.94 (s, 3H), 3.76˜3.57 (m, 5H), 3.45˜3.43 (m, 2H),3.28 (t, J=6.4 Hz, 1H), 3.21 (t, J=6.4 Hz, 1H), 2.17˜2.05 (m, 2H),1.93˜1.90 (m, 2H), 1.33 (d, J=6.4 Hz, 3H).

2-{1-[3-(3,4-Dimethoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

18% yield. LC-MS: m/z=440.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 6.85 (m, 2H), 6.74 (s, 1H), 4.12˜4.09 (m, 2H), 3.90 (s, 3H), 3.88(s, 3H), 3.80˜3.68 (m, 3H), 3.63˜3.57 (m, 2H), 3.49˜3.41 (m, 2H), 3.32(t, J=6.4 Hz, 1H), 3.23 (t, J=6.0 Hz, 1H), 2.13˜2.06 (m, 2H), 1.93˜1.90(m, 2H), 1.34 (d, J=6.4 Hz, 3H).

2-{1-[3-(4-Fluoro-3-methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z=428.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.85 (s,1H), 7.06 (dd, J=8.4 Hz, J=10.5 Hz, 1H), 6.85˜6.81 (m, 2H), 4.14˜4.09(m, 2H), 3.92 (s, 3H), 3.81˜3.71 (m, 3H), 3.65˜3.57 (m, 2H), 3.47˜3.42(m, 2H), 3.35˜3.33 (m, 1H), 3.24 (m, 1H), 2.14˜2.10 (m, 2H), 1.95˜1.90(m, 2H), 1.35 (d, J=6.6 Hz, 3H).

2-{1-[3-(3,5-Difluoro-4-methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

15% yield. LC-MS: m/z=446.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.85 (s,1H), 6.86˜6.83 (m, 2H), 4.13˜4.09 (m, 2H), 3.99 (s, 3H), 3.77˜3.71 (m,2H), 3.67˜3.57 (m, 3H), 3.48˜3.41 (m, 2H), 3.29˜3.20 (m, 2H), 2.13˜2.08(m, 2H), 1.95˜1.90 (m, 2H), 1.34 (d, J=8.8 Hz, 3H).

2-{1-[3-(3-Methoxy-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

5% yield. LC-MS: m/z=410.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.13 (s, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.82˜6.89 (m, 2H), 4.11˜4.09(m, 2H), 3.82 (s, 3H), 3.79˜3.70 (m, 2H), 3.63˜3.57 (m, 2H), 3.46˜3.40(m, 2H), 3.36˜3.34 (m, 1H), 3.33˜3.26 (m, 1H), 2.23 (s, 1H), 2.12˜2.05(m, 2H), 1.93˜1.90 (m, 2H), 1.33 (d, J=6.4 Hz, 3H).

2-{1-[3-(4-Methoxy-3-methyl-phenyl)-azetidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

21% yield. LC-MS: m/z=424.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.85 (s,1H), 7.09˜7.06 (m, 2H), 6.80 (d, J=7.8 Hz, 1H), 4.14˜4.09 (m, 2H), 3.84(s, 3H), 3.78˜3.67 (m, 3H), 3.66˜3.57 (m, 2H), 3.49˜3.42 (m, 2H),3.34˜3.29 (m, 1H), 3.24˜3.22 (m, 1H), 2.24 (s, 3H), 2.14˜2.08 (m, 2H),1.96˜1.91 (m, 2H), 1.34 (d, J=6.6 Hz, 3H).

2-[1-(3-Benzo[1,3]dioxol-5-yl-azetidin-1-yl)-ethyl]-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

10% yield. LC-MS: m/z=424.2 [M+1]⁺. ¹H NMR (300 MHz, CDCl₃): δ 7.85 (s,1H), 6.81˜6.70 (m, 3H), 5.97 (s, 2H), 4.14˜4.10 (m, 2H), 3.77˜3.70 (m,3H), 3.68˜3.58 (m, 2H), 3.49˜3.41 (m, 2H), 3.29 (t, J=6.6 Hz, 1H), 3.22(t, J=6.0 Hz, 1H), 2.13˜2.09 (m, 2H), 1.95˜1.91 (m, 2H), 1.34 (d, J=6.6Hz, 3H).

2-{1-[3-(4-Methoxy-phenyl)-pyrrolidin-1-yl]-ethyl}-7-(tetrahydro-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one

6% yield. LC-MS: m/z=424.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s,1H), 7.17˜7.15 (d, J=7.6 Hz, 2H), 6.87˜6.84 (dd, J=2.4, 8.4 Hz, 2H),4.11˜4.08 (m, 2H), 3.79 (s, 3H), 3.62˜3.42 (m, 3H), 3.33˜3.39 (m, 2H),3.11˜3.04 (m, 1H), 2.90˜2.78 (m, 2H), 2.62˜2.57 (m, 1H), 2.35˜2.31 (m,1H), 2.11˜2.04 (m, 2H), 1.93˜1.90 (m, 3H), 1.25 (d, J=6.6 Hz, 3H).

In Vitro Testing PDE9 Inhibition Assay

A PDE9 assay may for example, be performed as follows: The assay isperformed in 60 uL samples containing a fixed amount of the relevant PDEenzyme (sufficient to convert 20-25% of the cyclic nucleotidesubstrate), a buffer (50 mM HEPES 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1mg/ml BSA, 225 pCi of ³H-labelled cyclic nucleotide substrate, tritiumlabeled cAMP to a final concentration of 5 nM and varying amounts ofinhibitors. Reactions are initiated by addition of the cyclic nucleotidesubstrate, and reactions are allowed to proceed for one hr at roomtemperature before being terminated through mixing with 15 uL 8 mg/mLyttrium silicate SPA beads (Amersham). The beads are allowed to settlefor one hr in the dark before the plates are counted in a Wallac 1450Microbeta counter. The measured signal can be converted to activityrelative to an uninhibited control (100%) and IC₅₀ values can becalculated using the Xlfit extension to EXCEL.

In the context of the present invention the assay was performed in 60 uLassay buffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20) containingenough PDE9 to convert 20-25% of 10 nM ³H-cAMP and varying amounts ofinhibitors. Following a 1 hour incubation the reactions were terminatedby addition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). Thebeads were allowed to settle for one hr in the dark before the plateswere counted in a Wallac 1450 Microbeta counter. IC₅₀ values werecalculated by non linear regression using XLfit (IDBS).

Results of the experiments showed that the tested compounds of theinvention inhibit the PDE9 enzyme with IC₅₀ values below 250 nM.

1. A compound having the structure (I)

wherein R2 is cyclized with either R1 or R3, wherein R1, R2 and R3 are:R1, when cyclized with R2, is

wherein R6 is selected from the group consisting of H, —CH₃, —C₂H₅, and—C₃H₇, wherein * denotes the cyclization point, and R1, when notcyclized, is selected from the group consisting of H and

wherein R6 is selected from the group consisting of H, —CH₃, —C₂H₅, and—C₃H₇ R2 is a compound selected from the group consisting of

wherein R7 and R11 independently are selected from the group consistingof H, —CH₃, —C₂H₅, and —C₃H₇ wherein * denotes the cyclization point,and R3, when cyclized with R2, is

wherein * denotes the cyclization point, and wherein R8 is selected fromthe group consisting of H, C₁-C₆ alkyl, branched C₃-C₆ alkyl, C₃-C₅cycloalkyl, C₆-C₁₀ aryl, substituted C₆-C₁₀ aryl, C₃-C₉ heteroaryl,substituted C₃-C₉ heteroaryl, C₁-C₆ alkoxy, branched C₃-C₆ alkoxy, C₃-C₆cycloalkoxy, C₆-C₁₀ aryloxy, substituted C₆-C₁₀ aryloxy, C₃-C₉heteroaryloxy, substituted C₃-C₉ heteroaryloxy; and R3, when notcyclized, is

wherein R9 is selected from the group consisting of H, —CH₃, and —C₂H₅;and R10 is selected from the group consisting of C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, C₃-C₉ heteroaryl, substituted C₃-C₉ heteroarylR4 is selected from the group consisting of C₆-C₁₀ aryl, substitutedC₆-C₁₀ aryl, C₃-C₉ heteroaryl, substituted C₃-C₉ heteroaryl, C₃-C₆heterocyclyl, substituted C₃-C₆ heterocyclyl, C₃-C₆ cycloalkyl, andsubstituted C₃-C₆ cycloalkyl; R5 is selected from the group consistingof hydrogen, F, Cl, CN, —CH₃, —C₂H₅, —C₃H₇, and —CF₃; A is absent or—CH₂— and tautomers and pharmaceutically acceptable acid addition saltsthereof, and polymorphic forms thereof provided that the compound is not2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;[4-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(4-methylpyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(6-methoxy-2-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3S,4S)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3R,4R)-1-benzyl-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3S,4S)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3R,4R)-4-methylpyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;4-[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]benzonitrile;2-[(3S,4S)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3R,4R)-1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-oneor2-[4-methyl-1-(pyrazin-2-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one.2. The compound of claim 1 wherein the one or more heteroaryls of R4, R8and R10 independently of each other comprise one or two nitrogen.
 3. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of7-(4-fluorophenyl)-2-[4-methyl-1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3,6-dihydro-2H-pyran-4-yl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[1-[(6-methoxy-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[4-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(3-pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[1-[(2,4-difluorophenyl)methy]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-[4-(trifluoromethoxy)phenyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[1-[(4-fluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-3Himidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(2,4-difluorophenyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-[[4-(trifluoromethoxy)phenyl]methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-pyridyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[[3-(4-methoxyphenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(2-chloro-4-methoxy-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(quinoxalin-6-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(4-fluorophenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(4-methoxyphenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(4-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(2-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(4-fluorophenoxyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(pyrimidin-5-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[[4-(diethylamino)phenyl]methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-(2-furylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-(1H-imidazol-2-ylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;7-(4-fluorophenyl)-2-[(3R,4R)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(2-chloro-4-fluoro-phenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(4-dimethylaminophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(p-tolylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(benzyloxymethyl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(2,6-difluorophenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-(cyclohexylmethyl)-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one7-tetrahydropyran-4-yl-2-[[3-[4-(trifluoromethoxy)phenoxy]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(4-dimethylaminophenyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(3-pyridylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(2,6-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3-phenoxyazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-ethyl-4-methyl-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-[(4-fluorophenyl)methoxy]azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-[(5-methyl-2-furyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(5-chloro-2-furyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-fluorophenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3-phenylazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(4-methylphenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methyl-pyrrolidin-3-yl)-7-(4-piperidyl)-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(5-fluoro-3-pyridyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(2-pyridyl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(4-isopropylphenoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(3,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(4-chlorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3S,4S)-1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[[6-(dimethylamino)-3-pyridyl]methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;methyl5-[[3-methyl-4-(4-oxo-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-2-yl)pyrrolidin-1-yl]methyl]thiophene-2-carboxylate;7-tetrahydropyran-4-yl-2-[[3-[5-(trifluoromethyl)-2-pyridyl]azetidin-1-yl]methyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(3-pyridyloxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3R,4R)-1-[(2,4-difluorophenyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(1R)-1-[3-(4-methoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-fluorophenoxy)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-[(5-methyl-2-thienyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imdazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(5-chloro-2-thienyl)methyl]-4-methyl-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-[(4-pyrrolidin-1-ylphenyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-(1-benzyl-4-methoxy-pyrrolidin-3-yl)-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methyl-1-(pyrimidin-4-ylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-hydroxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[(4-fluorophenyl)methyl]-4-methoxy-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methoxy-1-(p-tolylmethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(p-tolylmethoxy)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3-benzylazetidin-1-yl)methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3S,4S)-1-benzyl-4-methoxy-pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-methylphenoxy)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-[(4-methoxyphenoxy)methyl]azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[(3-pyrimidin-2-ylazetidin-1-ylmethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-pyrrolidin-1-ylphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-benzyl-4-(trifluoromethyl)pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[[3-(5-pyrrolidin-1-ylpyrimidin-2-yl)azetidin-1-yl]methyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-dimethylaminophenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[4-methoxy-1-[(4-methoxyphenyl)methyl]pyrrolidin-3-yl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-(3-phenylazetidin-1-yl)ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(3-fluoro-4-methoxy-phenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(2-fluoro-4-methoxy-phenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-(4-ethoxyphenyl)azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;2-[1-[3-[(4-methoxyphenyl)methyl]azetidin-1-yl]ethyl]-7-tetrahydropyran-4-yl-3H-imidazo[5,1-f][1,2,4]triazin-4-one;and7-tetrahydropyran-4-yl-2-[1-[3-[4-(trifluoromethoxy)phenyl]azetidin-1-yl]ethyl]-3H-imidazo[5,1-f][1,2,4]triazin-4-oneand a pharmaceutically acceptable acid addition salt thereof. 4.(canceled)
 5. (canceled)
 6. (canceled)
 7. A method of treating a subjectsuffering from a neurodegenerative disorder, wherein theneurodegenerative disorder is selected from the group consisting ofAlzheimer's disease, mental retardation, CIAS,attention-deficit/hyperactivity disorder, age-related cognitive decline,and substance-induced psychotic disorder.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, and one or more pharmaceutically acceptable carriers,diluents and excipients.
 9. The method of claim 7 wherein thesubstance-induced psychotic disorder is psychosis induced by alcohol,amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, orphencyclidine.